Ring-contracted morphinans and the use thereof

ABSTRACT

The application is directed to compounds of Formula (I) or (IA) and pharmaceutically acceptable salts and solvates thereof, wherein R 1  R 2 ,  R3  and G are defined as set forth in the specification. The invention is also directed to use of compounds of Formula (I) or(IA), and the pharmaceutically acceptable salts and solvates thereof, to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This application is in the field of medicinal chemistry. The applicationrelates to novel ring-contracted morphinans and pharmaceuticalcompositions comprising one or more of these compounds. The applicationalso relates to methods of using ring-contracted morphinans.

2. Description of the Related Art

Pain is the most common symptom for which patients seek medical adviceand treatment. While acute pain is usually self-limited, chronic paincan persist for 3 months or longer and lead to significant changes in apatient's personality, lifestyle, functional ability and overall qualityof life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C.Bennett and F. Plum eds., 20th ed. 1996).

Pain has traditionally been managed by administering either a non-opioidanalgesic (such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflunisal ornaproxen), or an opioid analgesic (such as morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, oxymorphone, orbuprenorphine).

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes are known as μ, δ and κ. Asopiates have a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as endorphins, enkephalins, and dynorphins, respectively.Additional experimentation has led to the identification of the opioidreceptor-like (ORL-1) receptor, which has a high degree of homology tothe known opioid receptor classes. This more recently discoveredreceptor was classified as an opioid receptor based only on structuralgrounds, as the receptor did not exhibit pharmacological homology. Itwas initially demonstrated that non-selective ligands having a highaffinity for μ, δ and κ receptors had low affinity for the ORL-1receptor. This characteristic, along with the fact that an endogenousligand had not yet been discovered, led to the ORL-1 receptor beingdesignated as an “orphan receptor”.

Kappa (κ) opioid receptor agonists have been evaluated as alternativesto existing analgesics for the treatment of pain. Centrally penetratingκ agonists produce antinociceptive effects in conventional preclinicalassays of basal, inflammatory and neuropathic pain (Vanderah et al., J.Pharmacol. Exp. Ther. 310:326-333 (2004); Negus et al.,Psychopharmacology (Berl) 210:149-159 (2010)). However, centrallypenetrating κ agonists can also produce undesirable side-effects, suchas sedative and psychotomimetic effects (Pande et al., Clin.Neuropharmacol. 19:92-97 (1996); Pande et al., Clin. Neuropharmacol.19:451-456 (1996); and Wadenberg, CNS Drug Rev. 9:187-198 (2003)).

Opioid receptor agonists that do not readily cross the blood-brainbarrier are peripherically restricted and distribute poorly to thecentral nervous system after systemic administration. Such compoundswould retain an ability to produce analgesia by acting on peripheralopioid receptors, such as peripheral κ-opioid receptors, but theirpotency to produce centrally mediated side-effects would be reduced.

There is a need for effective analgesics that work by acting on opioidreceptors. There is also a need for analgesics that work by acting onperipheral opioid receptors. There is also a need for analgesics thatwork by acting on central opioid receptors. There is also a need foranalgesics that work by acting on κ-opioid receptors. There is also aneed for analgesics that work by acting-on peripheral κ-opioidreceptors.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides compounds represented byFormulae I, IA, and II-XVI, below, and the pharmaceutically acceptablesalts and solvates thereof, collectively referred to herein as“Compounds of the Invention” (each is individually referred tohereinafter as a “Compound of the Invention”).

In another aspect, the present disclosure provides the use of Compoundsof the Invention as synthesis intermediates.

In another aspect, the present disclosure provides the use of Compoundsof the Invention as modulators of one or more opioid receptors.Specifically, the present disclosure provides the use of Compounds ofthe Invention as modulators of μ, δ, κ, and/or ORL-1 opioid receptors,and especially modulators of μ and/or κ opioid receptors.

In another aspect, the present disclosure provides a method of treatingor preventing a disorder responsive to the modulation of one or moreopioid receptors in a patient, comprising administering to the patientan effective amount of a Compound of the Invention.

In another aspect, the present disclosure provides a use of a Compoundof the Invention as an analgesic to treat or prevent pain; or as anagent to treat or prevent withdrawal from alcohol or drug addiction; oras an agent to treat or prevent addictive disorders; or as an agent totreat a pruritic condition; or as an agent to treat or preventconstipation; or as an agent to treat or prevent diarrhea (each of pain,alcohol withdrawal, drug withdrawal, addictive disorders, pruritis,constipation, and diarrhea being a “Condition”).

The present invention further provides methods of treating or preventinga Condition, comprising administering to a patient in need thereof atherapeutically effective amount of a Compound of the Invention. Incertain embodiments, the Condition is pain (including acute pain,chronic pain (which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain), and surgical pain). TheCompounds of the Invention are particularly useful for treating orpreventing chronic pain.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a Compoundof the Invention and one or more pharmaceutically acceptable carriers.Such compositions are useful for treating or preventing a Condition in apatient.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of a disorder responsive tothe modulation of one or more opioid receptors. Preferably, the disorderis responsive to modulation of the μ-opioid receptor or the κ-opioidreceptor, or to modulation of both the μ-opioid receptor and theκ-opioid receptor.

In another aspect, the present disclosure provides a method ofmodulating one or more opioid receptors in a patient in need of saidmodulation, comprising administering to the patient an opioid receptormodulating amount of a Compound of the Invention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of one or more Conditionsin a patient in need of said treatment or prevention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of pain in a patient, suchas acute pain, chronic pain (which includes but is not limited to,neuropathic pain, postoperative pain, and inflammatory pain), orsurgical pain.

In another aspect, the present disclosure provides Compounds of theInvention for use in modulation of one or more opioid receptors in apatient.

In another aspect, the present disclosure provides use of Compounds ofthe Invention in the manufacture of a medicament for treating orpreventing a disorder responsive to the modulation of one or more opioidreceptors.

In another aspect, the present disclosure provides use of Compounds ofthe Invention in the manufacture of a medicament for modulating of oneor more opioid receptors in a patient. Preferably, the μ- or κ-opioidreceptor is modulated, or both the μ- and κ-opioid receptors aremodulated.

In another aspect, the present disclosure provides Compounds of theInvention for use as a medicament.

In another aspect, the present disclosure provides use of a Compound ofthe Invention in the manufacture of a medicament for treating orpreventing a Condition in a patient.

In another aspect, the present disclosure provides use of a Compound ofthe Invention in the manufacture of a medicament for treating orpreventing pain in a patient, such as acute pain, chronic pain, orsurgical pain.

In another aspect, the present disclosure provides a pharmaceuticalcomposition, comprising a Compound of the Invention for treating orpreventing a disorder responsive to the modulation of one or more opioidreceptors.

The present invention further provides methods for preparing apharmaceutical composition, comprising admixing a Compound of theInvention and a pharmaceutically acceptable carrier to form thepharmaceutical composition.

In another aspect, the present invention provides radiolabeled Compoundsof the Invention, especially ¹H, ¹¹C and ¹⁴C radiolabeled Compounds ofthe Invention, and the use of such compounds as radioligands to detectbinding to an opioid receptor in screening assays.

In another aspect, the present invention provides a method for screeninga candidate compound for the ability to bind to an opioid receptor,comprising a) introducing a fixed concentration of a radiolabeledCompound of the Invention to the receptor under conditions that permitbinding of the radiolabeled compound to the receptor to form a complex;b) titrating the complex with a candidate compound; and c) determiningthe binding of the candidate compound to said receptor.

In a further aspect, the invention relates to a kit, comprising asterile container containing an effective amount of a Compound of theInvention and instructions for therapeutic use.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Certain Compounds of the Invention are useful for modulating apharmacodynamic response from one or more opioid receptors (μ, δ, κ,ORL-1) either centrally or peripherally, or both. The pharmacodynamicresponse may be attributed to the compound either stimulating(agonizing) or inhibiting (antagonizing) the one or more receptors.Certain Compounds of the Invention may antagonize one or more opioidreceptors, while also agonizing one or more other receptors. Compoundsof the Invention having agonist activity may be either full or partialagonists.

One aspect of the invention is based on the use of certain Compounds ofthe Invention as synthesis intermediates.

In one embodiment, Compounds of the Invention are compounds representedby Formula I:

and the pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is hydrogen, hydroxy, halo, cyano, carboxy, or aminocarbonyl; oralkyl, alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy, any of whichis optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups; or —O-PG, wherein PG is a hydroxylprotecting group;

R² is

(a) hydrogen or carboxamido; or

(b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylalkyl, alkylcarbonyl,alkoxycarbonyl, (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups;

R³ is hydrogen, hydroxy, or halo; or alkoxy, alkylamino, ordialkylamino, any of which is optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups;

each R⁴ is independently selected from the group consisting of hydroxy,halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino,carboxy, alkoxy, and alkoxycarbonyl;

G is selected from the group consisting of G¹, G², G³, and G⁴, wherein

G¹ is —C(═O)OR⁵,

G² is —C(═O)NR⁶R⁷,

G³ is —NR⁸R⁹, and

G⁴ is —CN, wherein

R⁵ is hydrogen or alkyl;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (aminocarbonyl)alkyl,(alkylaminocarbonyl)alkyl, (dialkylaminocarbonyl)alkyl, carboxyalkyl,(alkoxycarbonyl)alkyl, and guanidinoalkyl, wherein the cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl portions are optionallysubstituted with one or more R⁴ groups; or

R⁶ and R⁷ together with the nitrogen atom to which they are attachedform an optionally substituted heterocyclic ring; and

R⁸ and R⁹ are each independently selected form the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylalkyl, (cycloalkyl)-C(═O)—,(cycloalkenyl)-C(═O)—, heterocyclo-C(═O)—, aryl-C(═O)—,heteroaryl-C(═O)—, (cycloalkyl)alkyl-C(═O)—, (cycloalkenyl)alkyl-C(═O)—,(heterocyclo)alkyl-C(═O)—, arylalkyl-C(═O)—, (heteroaryl)alkyl-C(═O)—,(cycloalkyl)-NR¹⁰—C(═O)—, (cycloalkenyl)-NR¹⁰—C(═O)—,heterocyclo-NR¹⁰—C(═O)—, aryl-NR¹⁰—C(═O)—, heteroaryl-NR¹⁰—C(═O)—,(cycloalkyl)alkyl-NR¹⁰—C(═O)—, (cycloalkenyl)alkyl-NR¹⁰—C(═O)—,(heterocyclo)alkyl-NR¹⁰—C(═O)—, arylalkyl-NR¹⁰—C(═O)—,(heteroaryl)alkyl-NR¹⁰—C(═O)—, (cycloalkyl)-SO₂—, (cycloalkenyl)-SO₂—,heterocyclo-SO₂—, aryl-SO₂—, heteroaryl-SO₂—, (cycloalkyl)alkyl-SO₂—,(cycloalkenyl)alkyl-SO₂—, (heterocyclo)alkyl-SO₂—, arylalkyl-SO₂—,(heteroaryl)alkyl-SO₂—, R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—,R^(10a)—SO₂—, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(aminocarbonyl)alkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, carboxyalkyl, (alkoxycarbonyl)alkyl, andguanidinoalkyl, wherein the cycloalkyl, cycloalkenyl, heterocyclo, aryl,and heteroaryl portions are optionally substituted with one or more R⁴groups;

R¹⁰ is hydrogen or alkyl;

R^(10a) is alkyl, alkenyl, or alkenyl; or

R¹⁰ and R^(10a) together with the nitrogen atom to which they areattached form an optionally substituted heterocyclic ring; and

R⁸ and R⁹ together with the nitrogen atom to which they are attachedform an optionally substituted heterocyclic ring.

In another embodiment, the invention provides compounds represented byFormula IA:

and the pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is hydrogen, hydroxy, halo, cyano, carboxy, or aminocarbonyl; oralkyl, alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy, any of whichis optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups; or —O-PG, wherein PG is a hydroxylprotecting group;

R² is

(a) hydrogen or carboxamido; or

(b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylalkyl, alkylcarbonyl,alkoxycarbonyl, (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups;

R³ is hydrogen, hydroxy, or halo; or alkoxy, alkylamino, ordialkylamino, any of which is optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups;

each R⁴ is independently selected from the group consisting of hydroxy,halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino,carboxy, alkoxy, and alkoxycarbonyl;

G is selected from the group consisting of G¹, G², G³, and G⁴, wherein

G¹ is —C(═O)OR⁵,

G² is —C(═O)NR⁶R⁷,

G³ is —NR⁸R⁹, and

G⁴ is —CN, wherein

R⁵ is hydrogen or alkyl;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylalkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (aminocarbonyl)alkyl,(alkylaminocarbonyl)alkyl, (dialkylaminocarbonyl)alkyl, carboxyalkyl,(alkoxycarbonyl)alkyl, guanidinoalkyl, hydroxyalkyl, and alkoxyalkyl,wherein the cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroarylportions are optionally substituted with one or more R⁴ groups; or

R⁶ and R⁷ together with the nitrogen atom to which they are attachedform an optionally substituted heterocyclic ring; and

R⁸ and R⁹ are each independently selected form the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylalkyl, (cycloalkyl)-C(═O)—,(cycloalkenyl)-C(═O)—, heterocyclo-C(═O)—, aryl-C(═O)—,heteroaryl-C(═O)—, (cycloalkyl)alkyl-C(═O)—, (cycloalkenyl)alkyl-C(═O)—,(heterocyclo)alkyl-C(═O)—, arylalkyl-C(═O)—, (heteroaryl)alkyl-C(═O)—,(cycloalkyl)-NR¹⁰—C(═O)—, (cycloalkenyl)-NR¹⁰—C(═O)—,heterocyclo-NR¹⁰—C(═O)—, aryl-NR¹⁰—C(═O)—, heteroaryl-NR¹⁰—C(═O)—,(cycloalkyl)alkyl-NR¹⁰—C(═O)—, (cycloalkenyl)alkyl-NR¹⁰—C(═O)—,(heterocyclo)alkyl-NR¹⁰—C(═O)—, arylalkyl-NR¹⁰—C(═O)—,(heteroaryl)alkyl-NR¹⁰—C(═O)—, (cycloalkyl)-SO₂—, (cycloalkenyl)-SO₂—,heterocyclo-SO₂—, aryl-SO₂—, heteroaryl-SO₂—, (cycloalkyl)alkyl-SO₂—,(cycloalkenyl)alkyl-SO₂—, (heterocyclo)alkyl-SO₂—, arylalkyl-SO₂—,(heteroaryl)alkyl-SO₂—, R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—,R^(10a)—SO₂—, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(aminocarbonyl)alkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, carboxyalkyl, (alkoxycarbonyl)alkyl,guanidinoalkyl, hydroxyalkyl, and alkoxyalkyl, wherein the cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl portions are optionallysubstituted with one or more R⁴ groups;

R¹⁰ is hydrogen or alkyl;

R^(10a) is alkyl, alkenyl, or alkenyl; or

R¹⁰ and R^(10a) together with the nitrogen atom to which they areattached form an optionally substituted heterocyclic ring; and

R⁸ and R⁹ together with the nitrogen atom to which they are attachedform an optionally substituted heterocyclic ring.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula II:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula III:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula V:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VI:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VIII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IX:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae X to XV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, and G are as defined for Formula I or IA.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R¹ is H, hydroxy, halo, cyano,carboxy, or aminocarbonyl (i.e., —C(═O)NH₂). In another embodiment, R¹is hydroxy, cyano, or aminocarbonyl. In another embodiment, R¹ ishydroxy. In another embodiment, R¹ is cyano. In another embodiment, R¹is aminocarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R¹ is alkyl, alkenyl, alkynyl,alkoxy, alkenyloxy, or alkynyloxy, any of which is optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein saidaryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R⁴ groups.In another embodiment, R¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, or C₂₋₆ alkynyloxy, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, halo(C₁₋₆)alkyl,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, carboxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, 5- or6-membered heterocyclo, C₃₋₇ cycloalkyl, and C₃₋₇ cycloalkenyl, whereinsaid aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R⁴ groups.Useful R⁴ groups include hydroxy, halo, C₁₋₆ alkyl, halo(C₁₋₆)alkyl,cyano, nitro, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, carboxy, C₁₋₆alkoxy, and C₁₋₆ alkoxycarbonyl, and preferably hydroxy, halo, C₁₋₄alkyl, halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino, di(C₁₋₄alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl, such ashydroxy, methyl, ethyl, halo, trifluoromethyl, cyano, nitro, amino,methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxy,ethoxy, methoxycarbonyl, and ethoxycarbonyl. In another embodiment, R¹is C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, or C₂₋₆ alkynyloxy, any of which areoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, halo(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl. In another embodiment, R¹ is unsubstituted C₁₋₆alkoxy, unsubstituted C₂₋₆ alkenyloxy, or unsubstituted C₂₋₆ alkynyloxy.In another embodiment, R¹ is unsubstituted methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, tert-butoxy, iso-butoxy, or sec-butoxy, andadvantageously R¹ is unsubstituted methoxy. In another embodiment, R¹ isunsubstituted ethenoxy, propenoxy, isopropenoxy, butenoxy, orsec-butenoxy. In another embodiment, R¹ is unsubstituted ethynoxy,propynoxy, butynoxy, or 2-butynoxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R¹ is unsubstituted C₁₋₆alkoxy, hydroxy, cyano, or aminocarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R¹ is unsubstituted C₁₋₆alkoxy or hydroxy, and preferably unsubstituted C₁₋₄ alkoxy or hydroxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is hydrogen or carboxamido.In this aspect of the invention, preferably R² is hydrogen, —CONH₂,—CON(H)C₁₋₄ alkyl, —CON(C₁₋₄ alkyl)₂, or —CON(H)Ph, and more preferablyR² is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,(cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R⁴ groups. In oneembodiment, R² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkenyl, 5- or 6-membered heterocyclo, C₆₋₁₀ aryl,5- or 6-membered heteroaryl, C₃₋₇ cycloalkyl(C₁₋₄)alkyl, C₃₋₇cycloalkenyl(C₁₋₄)alkyl, 5- or 6-membered heterocyclo(C₁₋₄)alkyl, C₆₋₁₀aryl(C₁₋₄)alkyl, 5- or 6-membered heteroaryl(C₁₋₄)alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₆₋₁₀ aryl(C₁₋₄)alkoxycarbonyl, or5- or 6-membered heteroaryl(C₁₋₄)alkoxycarbonyl, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, C₁₋₆ alkyl, halo,halo(C₁₋₆)alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, carboxy,C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 5- or 6-membered heterocyclo, C₃₋₇ cycloalkyl, and C₃₋₇cycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups. Useful R⁴ groups are those describedabove in connection with R¹.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, 5- or6-membered heterocyclo, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₃₋₇(cycloalkyl)(C₁₋₄ alkyl, C₃₋₇ (cycloalkenyl)(C₁₋₄ alkyl, 5- or6-membered heterocyclo(C₁₋₄)alkyl, C₆₋₁₀ aryl(C₁₋₄)alkyl, 5- or6-membered heteroaryl(C₁₋₄ alkyl, C₁₋₄ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₆₋₁₀ aryl(C₁₋₄)alkoxycarbonyl, or 5- or 6-memberedheteroaryl(C₁₋₄ alkoxycarbonyl, any of which is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄alkoxycarbonyl, and preferably optionally substituted with 1 or 2substituents, each independently selected from the group consisting ofhydroxy, methyl, ethyl, halo, trifluoromethyl, amino, methylamino,ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy,methoxycarbonyl, and ethoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is C₁₋₆ alkyl, andpreferably C₁₋₄ alkyl, which is unsubstituted or substituted with 1, 2,or 3 substituents each independently selected from the group consistingof hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl. Inanother embodiment, R² is methyl, ethyl, trifluoromethyl, or2,2,2-trifluoroethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is unsubstituted C₁₋₆alkyl, and preferably unsubstituted C₁₋₄ alkyl, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, or tert-butyl, and more preferably methylor ethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is C₃₋₇(cycloalkyl)(C₁₋₄)alkyl or C₃₋₇ (cycloalkenyl)(C₁₋₄)alkyl, andespecially C₃₋₇ (cycloalkyl)(C₁₋₄)alkyl, such as cyclopropyl(C₁₋₄)alkyl,cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl,optionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, C₁₋₄ alkyl, halo,halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy,C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl, and preferably optionallysubstituted with 1 or 2 substituents, each independently selected fromthe group consisting of hydroxy, methyl, ethyl, halo, trifluoromethyl,amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy,methoxy, ethoxy, methoxycarbonyl, and ethoxycarbonyl. Preferably, R² isunsubstituted cyclopropyl(C₁₋₄)alkyl. In another embodiment, R² isunsubstituted cyclohexyl(C₁₋₄)alkyl, such as cyclohexylmethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is unsubstituted(cyclopropyl)methyl, 2-(cyclopropyl)ethyl or 3-(cyclopropyl)propyl. Inanother embodiment, R² is unsubstituted (cyclopropyl)methyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is C₁₋₆ alkyl, andpreferably C₁₋₄ alkyl, substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of halo (such asfluoro), halo(C₁₋₄)alkyl (such as, for example, trifluoro(C₁₋₂)alkyl),phenyl, and heterocyclo (such as tetrahydropyranyl). In one embodimentof this aspect of the invention, R² is benzyl, phenethyl,3-phenylpropyl, tetrahydropyran-4-ylmethyl, 2,2,2-trifluoroethyl,2-fluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or2,2-difluoroethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R² is C₂₋₆ alkenyl, andpreferably C₂₋₄ alkenyl, which is unsubstituted or substituted with 1,2, or 3 substituents, each independently selected from the groupconsisting of C₁₋₄ alkyl (such as methyl), halo (such as fluoro),halo(C₁₋₄)alkyl (such as, for example, trifluoro(C₁₋₂)alkyl), phenyl,and heterocyclo (such as tetrahydropyranyl). In one embodiment of thisaspect of the invention, R² is 3-methyl-but-2-enyl, 3-methylbut-3-enyl,or 4-phenylbut-2-enyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R³ is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R³ is hydroxy or halo. Inanother embodiment, R³ is hydroxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R³ is alkoxy, alkylamino, ordialkylamino, any of which is optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R³ is C₁₋₆ alkoxy, C₁₋₆alkylamino, or di(C₁₋₆)alkylamino, any of which is optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, halo, halo(C₁₋₆)alkyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, carboxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, 5- or6-membered heterocyclo, C₃₋₇ cycloalkyl, and C₃₋₇ cycloalkenyl, whereinsaid aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R⁴ groups.Useful R⁴ groups are those described above in connection with R¹.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R³ is unsubstituted C₁₋₆alkoxy or C₁₋₆ alkoxy substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy,C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G¹, and is —C(═O)OR⁵,wherein R⁵ is hydrogen or alkyl. In one embodiment, R⁵ is hydrogen. Inanother embodiment, R⁵ is alkyl, and preferably C₁₋₆ alkyl, morepreferably C₁₋₄ alkyl, such as methyl or ethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G¹, and G¹ is selectedfrom the group consisting of

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is—C(═O)NR⁶R⁷, wherein R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(aminocarbonyl)alkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, carboxyalkyl, (alkoxycarbonyl)alkyl,(guanidino)alkyl, hydroxyalkyl, and alkoxyalkyl, wherein the cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl portions are optionallysubstituted with one or more R⁴ groups. In another embodiment, R⁶ and R⁷are each independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkenyl, 5- or 6-membered heterocyclo, phenyl, 5- or 6-memberedheteroaryl, (C₃₋₇ cycloalkyl)(C₁₋₆)-alkyl, (C₃₋₇cycloalkenyl)(C₁₋₆)-alkyl, (5- or 6-membered heterocyclo)(C₁₋₆)-alkyl,phenyl(C₁₋₆)alkyl, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, (C₁₋₆ alkylamino)(C₁₋₆)alkyl,(di(C₁₋₆alkyl)amino)(C₁₋₆)alkyl, (aminocarbonyl)(C₁₋₆)alkyl, (C₁₋₆alkylaminocarbonyl)(C₁₋₆)alkyl, (di(C₁₋₆)alkylaminocarbonyl)(C₁₋₆)alkyl,carboxy(C₁₋₆)alkyl, (C₁₋₆ alkoxycarbonyl)(C₁₋₆)alkyl,guanidino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, and (C₁₋₆alkoxy)(C₁₋₆)alkyl,wherein the cycloalkyl, cycloalkenyl, heterocyclo, phenyl, andheteroaryl portions are optionally substituted with one or more R⁴groups. In another embodiment, R⁶ is hydrogen or C₁₋₆ alkyl, and R⁷ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, 5- or6-membered heterocyclo, phenyl, 5- or 6-membered heteroaryl, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl, (5- or6-membered heterocyclo)(C₁₋₆)alkyl, phenyl(C₁₋₆)alkyl, (5- or 6-memberedheteroaryl)(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, (C₁₋₆ alkylamino)(C₁₋₆)alkyl,(di(C₁₋₆ alkyl)amino)(C₁₋₆)alkyl, (aminocarbonyl)(C₁₋₆)alkyl, (C₁₋₆alkylaminocarbonyl)(C₁₋₆)alkyl, (di(C₁₋₆)alkylaminocarbonyl)(C₁₋₆)alkyl,carboxy(C₁₋₆)alkyl, (C₁₋₆ alkoxycarbonyl)(C₁₋₆)alkyl,guanidino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, and (C₁₋₆ alkoxy)(C₁₋₆)alkyl,wherein the cycloalkyl, cycloalkenyl, heterocyclo, phenyl, andheteroaryl portions are optionally substituted with one or more R⁴groups. Suitable R⁴ groups include those defined in connection with R¹.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is selectedfrom the group consisting of

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is selectedfrom the group consisting of

wherein m is independently 0, 1, 2, or 3, and

R¹¹, R¹², and R¹³ are each independently selected from the groupconsisting of hydrogen, hydroxy, halogen, and C₁₋₄ alkyl. In oneembodiment, m is 0. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In one embodiment,R¹¹, R¹², and R¹³ each are hydrogen. In another embodiment, R¹¹ ishydrogen and R¹² and R¹³ are each independently selected from the groupconsisting of hydroxy, halogen (such as fluoro and chloro), and C₁₋₄alkyl (such as methyl or ethyl). In another embodiment, R¹¹ and R¹² bothare hydrogen, and R¹³ is selected from the group consisting of hydroxy,halogen (such as fluoro and chloro), and C₁₋₄ alkyl (such as methyl orethyl).

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is selectedfrom the group consisting of

wherein m is independently 0, 1, 2, or 3, and

R¹¹, R¹², and R¹³ are each independently selected from the groupconsisting of hydrogen, hydroxy, halogen, and C₁₋₄ alkyl. In oneembodiment, m is 0. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In one embodiment,R¹¹, R¹², and R¹³ each are hydrogen. In another embodiment, R¹¹ ishydrogen and R¹² and R¹³ are each independently selected from the groupconsisting of hydroxy, halogen (such as fluoro and chloro), and C₁₋₄alkyl (such as methyl or ethyl). In another embodiment, R¹¹ and R¹² bothare hydrogen, and R¹³ is selected from the group consisting of hydroxy,halogen (such as fluoro and chloro), and C₁₋₄ alkyl (such as methyl orethyl).

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is

wherein m, R¹¹, R¹², and R¹³ are as defined above.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is

wherein m, R¹¹, R¹², and R¹³ are as defined above.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is

wherein m, R¹¹, R¹², and R¹³ are as defined above.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is

wherein R¹¹, R¹², and R¹³ are as defined above, and m is 1, 2, or 3. Inanother embodiment, G² is

wherein R¹¹ and R¹² are as defined above, and m is 1, 2, or 3.

In another embodiment, G² is

and m is 1, 2, or 3.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is selectedfrom the group consisting of

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is selectedfrom the group consisting of

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and is —C(═O)NR⁶R⁷,wherein R⁶ and R⁷ together with the nitrogen atom to which they areattached form an optionally substituted heterocyclic ring. In oneembodiment, the heterocyclic ring is optionally substituted with 1, 2,or 3 independently selected substituents. In one embodiment, theoptionally substituted heterocyclic ring is an optionally substituted3-7 membered heterocyclic ring, and preferably an optionally substituted5- or 6-membered heterocyclic ring. In this aspect of the invention,useful heterocyclic rings include unsubstituted or substituted 5- or6-membered heterocyclic rings containing 1 or 2 nitrogen atoms andoptionally 1 or 2 heteroatoms selected from the group consisting of O,S, and NR¹⁴, wherein R¹⁴ is selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- or 6-membered heteroaryl,wherein said aryl and heteroaryl groups are optionally substituted with1, 2, or 3 independently selected R⁴ groups. In one embodiment, theheterocyclic ring is a substituted or unsubstituted 5-memberedheterocyclic ring containing 1 nitrogen atom, such as substituted orunsubstituted pyrrolidin-1-yl. In another embodiment, the heterocyclicring is a substituted or unsubstituted 6-membered heterocyclic ringcontaining 1 nitrogen atom and optionally 1 heteroarom selected from thegroup consisting of O, S, and NR¹⁴, wherein R¹⁴ is as defined above,such as, for example, a substituted or unsubstituted piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, and dioxidothiomorpholinyl.In another embodiment, the optionally substituted heterocyclic ring isan optionally substituted bicyclic ring system. In this aspect of theinvention, suitable heterocyclic rings include unsubstituted orsubstituted 7-10 membered bicyclic ring systems containing 1 or 2nitrogen atoms and optionally 1 or 2 heteroaroms selected from the groupconsisting of O, S, or NR¹⁴, wherein R¹⁴ is as defined above, such as,for example, isoindolin-2-yl and azabicyclo[3.2.1]octan-8-yl. Suitableoptional substituents include hydroxy, halo, C₁₋₄ alkyl,halo(C₁₋₄)alkyl, cyano, nitro, amino, aminocarbonyl, (C₁₋₄alkylamino)carbonyl, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, 5- or6-membered heterocyclo, C₆₋₁₀ aryl, and 5- or 6-membered heteroaryl,wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroarylare optionally substituted with 1, 2, or 3 independently selected R⁴groups; and preferably suitable optional substituents include hydroxy,halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro, amino, aminocarbonyl,(C₁₋₄ alkylamino)carbonyl, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy,C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl,pyrrolidin-1-yl, piperidin-1-yl, and phenyl, wherein said phenyl isoptionally substituted with 1, 2, or 3 independently selected R⁴ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², wherein R⁶ and R⁷together with the nitrogen atom to which they are attached form apyrrolidinyl, a piperidinyl, a piperazinyl, a morpholinyl, athiomorpholinyl, or a dioxidothiomorpholinyl ring, which isunsubstituted or substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of hydroxy, halo, C₁₋₄alkyl, halo(C₁₋₄)alkyl, cyano, nitro, amino, aminocarbonyl, (C₁₋₄alkylamino)carbonyl, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl,pyrrolidin-1-yl, piperidin-1-yl, and phenyl, wherein said phenyl isoptionally substituted with 1, 2, or 3 independently selected R⁴ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is selectedfrom the group consisting of

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G², and G² is

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G³, and is —NR⁸R⁹,wherein R⁸ and R⁹ are each independently selected form the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,(cycloalkyl)-C(═O)—, (cycloalkenyl)-C(═O)—, heterocyclo-C(═O)—,aryl-C(═O)—, heteroaryl-C(═O)—, (cycloalkyl)alkyl-C(═O)—,(cycloalkenyl)alkyl-C(═O)—, (heterocyclo)alkyl-C(═O)—, arylalkyl-C(═O)—,heteroarylalkyl-C(═O)—, (cycloalkyl)-NR¹⁰—C(═O)—,(cycloalkenyl)-NR¹⁰—C(═O)—, heterocyclo-NR¹⁰—C(═O)—, aryl-NR¹⁰—C(═O)—,heteroaryl-NR¹⁰—C(═O)—, (cycloalkyl)alkyl-NR¹⁰—C(═O)—,(cycloalkenyl)alkyl-NR¹⁰—C(═O)—, (heterocyclo)alkyl-NR¹⁰—C(═O)—,arylalkyl-NR¹⁰—C(═O)—, (heteroaryl)alkyl-NR¹⁰—C(═O)—, (cycloalkyl)-SO₂—,(cycloalkenyl)-SO₂—, heterocyclo-SO₂—, aryl-SO₂—, heteroaryl-SO₂—,(cycloalkyl)alkyl-SO₂—, (cycloalkenyl)alkyl-SO₂—,(heterocyclo)alkyl-SO₂—, arylalkyl-SO₂—, (heteroaryl)alkyl-SO₂—,R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—, R^(10a)—SO₂—, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (aminocarbonyl)alkyl,(alkylaminocarbonyl)alkyl, (dialkylaminocarbonyl)alkyl, carboxyalkyl,(alkoxycarbonyl)alkyl, guanidinoalkyl, hydroxyalkyl, and alkoxyalkyl,wherein the cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroarylportions are optionally substituted with one or more R⁴ groups; andwherein R¹⁰ is hydrogen or alkyl, and R^(10a) is alkyl, alkenyl, oralkynyl; or R¹⁰ and R^(10a) together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclic ring.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G³, wherein R⁸ and R⁹ areeach independently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl,5- or 6-membered heterocyclo, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl,(C₃₋₇ cycloalkyl)(C₁₋₆)alkyl, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl, (5- or6-membered heterocyclo)(C₁₋₆)alkyl, C₆₋₁₀ aryl(C₁₋₆)alkyl, (5- or6-membered heteroaryl)(C₁₋₆)alkyl, (C₃₋₇ cycloalkyl)-C(═O)—, (C₃₋₇cycloalkenyl)-C(═O)—, (5- or 6-membered heterocyclo)-C(═O)—, C₆₋₁₀aryl-C(═O)—, (5- or 6-membered heteroaryl)-C(═O)—, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl-C(═O)—, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl-C(═O)—,(5- or 6-membered heterocyclo)(C₁₋₆)alkyl-C(═O)—, C₆₋₁₀aryl(C₁₋₆)alkyl-C(═O)—, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl-C(═O)—,(C₃₋₇ cycloalkyl)-NR¹⁰—C(═O)—, (C₃₋₇ cycloalkenyl)-NR¹⁰—C(═O)—, (5- or6-membered heterocyclo)-NR¹⁰—C(═O)—, C₆₋₁₀ aryl-NR¹⁰—C(═O)—, (5- or6-membered heteroaryl)-NR¹⁰—C(═O)—, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (C₃₋₇cycloalkenyl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (5- or 6-memberedheterocyclo)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, C₆₋₁₀ aryl(C₁₋₆)alkyl-NR¹⁰—C(═O)—,(5- or 6-membered heteroaryl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (C₃₋₇cycloalkyl)-SO₂—, (C₃₋₇ cycloalkenyl)-SO₂—, (5- or 6-memberedheterocyclo)-SO₂—, C₆₋₁₀ aryl-SO₂—, (5- or 6-membered heteroaryl)-SO₂—,(C₃₋₇ cycloalkyl)(C₁₋₆)alkyl-SO₂—, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl-SO₂—,(5- or 6-membered heterocyclo)(C₁₋₆)alkyl-SO₂—, C₆₋₁₀aryl(C₁₋₆)alkyl-SO₂—, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl-SO₂—,R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—, R^(10a)—SO₂—, amino(C₁₋₆)alkyl,(C₁₋₆ alkylamino)(C₁₋₆)alkyl, (di(C₁₋₆)alkylamino)(C₁₋₆)alkyl,(aminocarbonyl)(C₁₋₆)alkyl, (C₁₋₆ alkylaminocarbonyl)(C₁₋₆)alkyl,(di(C₁₋₆)alkylaminocarbonyl)(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl, (C₁₋₆alkoxycarbonyl)(C₁₋₆)alkyl, guanidino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,and (C₁₋₆)alkoxy(C₁₋₆)alkyl, wherein R¹⁰ is hydrogen or C₁₋₆ alkyl, andR^(10a) is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, or R¹⁰ and R^(10a)together form a 5- or 6-membered heterocyclic ring optionallysubstituted with 1, 2, or 3 independently selected R⁴ groups; andwherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroarylportions thereof are optionally substituted with 1, 2, or 3independently selected R⁴ groups. Suitable R⁴ groups are those describedin connection with R¹.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G³, wherein R⁸ and R⁹ areboth hydrogen. In this embodiment, G is —NH₂.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G³, wherein R⁸ ishydrogen and R⁹ is selected from the group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, 5- or6-membered heterocyclo, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl, (5- or6-membered heterocyclo)(C₁₋₆)alkyl, C₆₋₁₀ aryl(C₁₋₆)alkyl, and (5- or6-membered heteroaryl)(C₁₋₆)alkyl, (C₃₋₇ cycloalkyl)-C(═O)—, (C₃₋₇cycloalkenyl)-C(═O)—, (5- or 6-membered heterocyclo)-C(═O)—, C₆₋₁₀aryl-C(═O)—, (5- or 6-membered heteroaryl)-C(═O)—, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl-C(═O)—, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl-C(═O)—,(5- or 6-membered heterocyclo)(C₁₋₆)alkyl-C(═O)—, C₆₋₁₀aryl(C₁₋₆)alkyl-C(═O)—, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl-C(═O)—,(C₃₋₇ cycloalkyl)-NR¹⁰—C(═O)—, (C₃₋₇ cycloalkenyl)-NR¹⁰—C(═O)—, (5- or6-membered heterocyclo)-NR¹⁰—C(═O)—, C₆₋₁₀ aryl-NR¹⁰—C(═O)—, (5- or6-membered heteroaryl)-NR¹⁰—C(═O)—, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (C₃₋₇cycloalkenyl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (5- or 6-memberedheterocyclo)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, C₆₋₁₀ aryl(C₁₋₆)alkyl-NR¹⁰—C(═O)—,(5- or 6-membered heteroaryl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (C₃₋₇cycloalkyl)-SO₂—, (C₃₋₇ cycloalkenyl)-SO₂—, (5- or 6-memberedheterocyclo)-SO₂—, C₆₋₁₀ aryl-SO₂—, (5- or 6-membered heteroaryl)-SO₂—,(C₃₋₇ cycloalkyl)(C₁₋₆)alkyl-SO₂—, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl-SO₂—,(5- or 6-membered heterocyclo)(C₁₋₆)alkyl-SO₂—, C₆₋₁₀aryl(C₁₋₆)alkyl-SO₂—, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl-SO₂—,R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—, R^(10a)—SO₂—, amino(C₁₋₆)alkyl,(C₁₋₆ alkylamino)(C₁₋₆)alkyl, (di(C₁₋₆)alkylamino)(C₁₋₆)alkyl,(aminocarbonyl)(C₁₋₆)alkyl, (C₁₋₆ alkylaminocarbonyl)(C₁₋₆)alkyl,(di(C₁₋₆)alkylaminocarbonyl)(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl, (C₁₋₆alkoxycarbonyl)(C₁₋₆)alkyl, guanidino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,and (C₁₋₆)alkoxy(C₁₋₆)alkyl, wherein R¹⁰ is hydrogen or C₁₋₆ alkyl, andR^(10a) is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, or R¹⁰ and R^(10a)together form a 5- or 6-membered heterocyclic ring optionallysubstituted with 1, 2, or 3 independently selected R⁴ groups; andwherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroarylportions thereof are optionally substituted with 1, 2, or 3independently selected R⁴ groups. Suitable R⁴ groups are those describedin connection with R¹. In another embodiment, R⁹ is selected from thegroup consisting of

wherein R¹⁵ is hydrogen, halogen, or C₁₋₄ alkyl. In one embodiment, R¹⁵is hydrogen. In another embodiment, R⁹ is

wherein R¹⁵ is hydrogen, halogen, or C₁₋₄ alkyl. In one embodiment, R¹⁵is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R⁸ and R⁹ are eachindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, 5- or6-membered heterocyclo, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl, (5- or6-membered heterocyclo)(C₁₋₆)alkyl, C₆₋₁₀ aryl(C₁₋₆)alkyl, and (5- or6-membered heteroaryl)(C₁₋₆)alkyl, (C₃₋₇ cycloalkyl)-C(═O)—, (C₃₋₇cycloalkenyl)-C(═O)—, (5- or 6-membered heterocyclo)-C(═O)—, C₆₋₁₀aryl-C(═O)—, (5- or 6-membered heteroaryl)-C(═O)—, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl-C(═O)—, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl-C(═O)—,(5- or 6-membered heterocyclo)(C₁₋₆)alkyl-C(═O)—, C₆₋₁₀aryl(C₁₋₆)alkyl-C(═O)—, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl-C(═O)—,(C₃₋₇ cycloalkyl)-NR¹⁰—C(═O)—, (C₃₋₇ cycloalkenyl)-NR¹⁰—C(═O)—, (5- or6-membered heterocyclo)-NR¹⁰—C(═O)—, C₆₋₁₀ aryl-NR¹⁰—C(═O)—, (5- or6-membered heteroaryl)-NR¹⁰—C(═O)—, (C₃₋₇cycloalkyl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (C₃₋₇cycloalkenyl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (5- or 6-memberedheterocyclo)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, C₆₋₁₀ aryl(C₁₋₆)alkyl-NR¹⁰—C(═O)—,(5- or 6-membered heteroaryl)(C₁₋₆)alkyl-NR¹⁰—C(═O)—, (C₃₋₇cycloalkyl)-SO₂—, (C₃₋₇ cycloalkenyl)-SO₂—, (5- or 6-memberedheterocyclo)-SO₂—, C₆₋₁₀ aryl-SO₂—, (5- or 6-membered heteroaryl)-SO₂—,(C₃₋₇ cycloalkyl)(C₁₋₆)alkyl-SO₂—, (C₃₋₇ cycloalkenyl)(C₁₋₆)alkyl-SO₂—,(5- or 6-membered heterocyclo)(C₁₋₆)alkyl-SO₂—, C₆₋₁₀aryl(C₁₋₆)alkyl-SO₂—, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl-SO₂—,R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—, R^(10a)—SO₂—, amino(C₁₋₆)alkyl,(C₁₋₆ alkylamino)(C₁₋₆)alkyl, (di(C₁₋₆)alkylamino)(C₁₋₆)alkyl,(aminocarbonyl)(C₁₋₆)alkyl, (C₁₋₆ alkylaminocarbonyl)(C₁₋₆)alkyl,(di(C₁₋₆)alkylaminocarbonyl)(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl, (C₁₋₆alkoxycarbonyl)(C₁₋₆)alkyl, guanidino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,and (C₁₋₆)alkoxy(C₁₋₆)alkyl, wherein R¹⁰ is hydrogen hydrogen or C₁₋₆alkyl, and R^(10a) is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, or R¹⁰and R^(10a) together form a 5- or 6-membered heterocyclic ringoptionally substituted with 1, 2, or 3 independently selected R⁴ groups;and wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, andheteroaryl portions thereof are optionally substituted with 1, 2, or 3independently selected R⁴ groups. In one embodiment, R⁸ and R⁹ are both

wherein each R¹⁵ is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₄ alkyl. In one embodiment, R¹⁵ is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G³, and is —NR⁸R⁹,wherein R⁸ and R⁹ together with the nitrogen atom to which they areattached form an optionally substituted heterocyclic ring. In oneembodiment, the optionally substituted heterocyclic ring is anoptionally substituted 3-7 membered heterocyclic ring, and preferably anoptionally substituted 5- or 6-membered heterocyclic ring. In thisaspect of the invention, useful heterocyclic rings include unsubstitutedor substituted 5- or 6-membered heterocyclic rings containing 1 or 2nitrogen atoms and optionally 1 or 2 heteroatoms selected from the groupconsisting of O, S, and NR¹⁶, wherein R¹⁶ is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- or 6-memberedheteroaryl, wherein said aryl and heteroaryl groups are optionallysubstituted with 1, 2, or 3 independently selected R⁴ groups. In oneembodiment, the heterocyclic ring is a substituted or unsubstituted5-membered heterocyclic ring containing 1 nitrogen atom, such assubstituted or unsubstituted pyrrolidin-1-yl. In another embodiment, theheterocyclic ring is a substituted or unsubstituted 6-memberedheterocyclic ring containing 1 nitrogen atom and optionally 1 heteroaromselected from the group consisting of O, S, and NR¹⁶, wherein R¹⁶ is asdefined above, such as, for example, a substituted or unsubstitutedpiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, anddioxidothiomorpholinyl. In another embodiment, the optionallysubstituted heterocyclic ring is an optionally substituted bicyclic ringsystem. In this aspect, suitable heterocyclic rings includeunsubstituted or substituted 7-10 membered bicyclic ring systemscontaining 1 or 2 nitrogen atoms and optionally 1 or 2 heteroaromsselected from the group consisting of O, S, or NR¹⁶, wherein R¹⁶ is asdefined above, such as, for example, isoindolin-2-yl andazabicyclo[3.2.1]octan-8-yl. Suitable optional substituents includehydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro, amino,aminocarbonyl, (C₁₋₄ alkylamino)carbonyl, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkenyl, 5- or 6-membered heterocyclo, C₆₋₁₀ aryl,and 5- or 6-membered heteroaryl, wherein said cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl are optionally substituted with 1, 2,or 3 independently selected R⁴ groups; and preferably suitable optionalsubstituents include hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano,nitro, amino, aminocarbonyl, (C₁₋₄ alkylamino)carbonyl, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, pyrrolidin-1-yl, piperidin-1-yl, andphenyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G³, which is selectedfrom the group consisting of

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G³, which is

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein G is G⁴, which is —CN.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R¹ is hydroxy or unsubstitutedC₁₋₆ alkoxy; R² is unsubstituted C₁₋₄ alkyl; C₁₋₄ alkyl substituted withhalo(C₁₋₄)alkyl; or cyclopropyl(C₁₋₄)alkyl, cyclobutyl(C₁₋₄ alkyl,cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄ alkyl, optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄alkoxycarbonyl; R³ is hydrogen or hydroxy; and G is as defined inconnection with any of Formulae I, IA, and II-XV. In one embodiment, R²is unsubstituted cyclopropyl(C₁₋₄)alkyl, and especiallycyclopropylmethyl. In another embodiment, R² is 2,2,2-trifluoroethyl. Inanother embodiment, R³ is hydroxy.

In another embodiment, Compounds of the Invention are compounds of TABLE1, and the pharmaceutically acceptable salts and solvates thereof.

TABLE 1 Compd No. Structure Chemical name  6

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2-guanidinoethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide  7

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(4-guanidinobutyl)-3a,8-dibydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 11

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)cyclo-penta[a]naphthalene-2-carboxamide 12

(2R,3aS,4R,9bS)-methyl-12- (cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxylate 14

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carboxylic acid 15

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carboxylic acid 16

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)-cyclopenta-[a]naphthalene-2-carboxylic acid 19

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)cyclo-penta[a]naphthalene-2-yl)(pyrrolidin-1- yl)methanone 20

((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)cyclo-penta[a]naphthalene-2-yl)(pyrrolidin-1- yl)methanone 21

(2R,3aS,4R,9bS)-2-amino-12- (cyclopropylmethyl)-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-3a-ol 22

(2R,3aS,4R,9bS)-2-amino-12- (cyclopropylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)- cyclopenta[a]naphthalene-3a,8-diol 25

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carbonitrile 26

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carbonitrile 28

(2S,3aS,4R,9bS)-2-amino-12- (cyclopropylmethyl)-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b- (epiminoethano)cyclopenta[a]naphthalene-3a-ol 29

(2S,3aS,4R,9bS)-2-amino-12- (cyclopropylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)- cyclopenta[a]naphthalene-3a,8-diol 30

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 31

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 33

(2R,3aS,4R,9bS)-N-benzyl-12- (cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b- (epiminoethano)cyclopenta[a]naphthalene-2-carboxamide 34

(2S,3aS,4R,9bS)-N-benzyl-12- (cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b- (epiminoethano)cyclopenta[a]naphthalene-2-carboxamide 35

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-isobutyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide36

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-isobutyl-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carboxamide 37

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-methylbenzyl)- 1,2,3,3a,4,5-hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2- carboxamide 38

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-methylbenzyl)- 1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene- 2-carboxamide 39

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 40

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-hydroxybenzyl)- 1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene- 2-carboxamide 41

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 42

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 43

(2R,3aS,4R,9bS)-N-(4-chlorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 44

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 45

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 46

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 47

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 48

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(4-fluorobenzyl)-3a,8-dihydroxy- 1,2,3,3a,4,5-hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2- carboxamide 49

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 50

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-phenethyl-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carboxamide 51

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide56

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(piperidin-1- yl)methanone 57

((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(piperidin-1- yl)methanone 58

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(morpholino)- methanone 59

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N,N-diethyl-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide62

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N,N-dimethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide64

(2R,3aS,4R,9bS)-N-(2-amino-2-oxoethyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy- 1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene- 2-carboxamide 66

2-((2R,3aS,4R,9bS)-12-(cyclopropyl- methyl)-3a,8-dihydroxy-N-methyl-1,2,3,3a,4,5-hexahydro-4,9b- (epiminoethano)cyclopenta[a]naphthalene-2-carboxamido)acetic acid 75

(2R,3aS,4R,9bS)-3a,8-dihydroxy-12- (2,2,2-tritluoroethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide76

(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclo-penta[a]naphthalene-2-carboxamide 77

(2R,3aS,4R,9bS)-3a,8-dihydroxy-12- methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene- 2-carboxamide 78

(2S,3aS,4R,9bS)-3a,8-dihydroxy-12- methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta- [a]naphthalene-2-carboxamide 79

N-((2S,3aS,4R,9bS)-12-(cyclopropyl- methyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalen-2-yl)benzamide80

(2R,3aS,4R,9bS)-2-(benzylamino)-12- (cyclopropylmethyl)-2,3,4,5-tetrahydro-4,9b-(epiminoethano)- cyclopenta-[a]naphthalene-3a,8(1H)-diol 81

(2R,3aS,4R,9bS)-12-(cyclopropyl- methyl)-2-(dibenzylamino)-2,3,4,5-tetrahydro-4,9b-(epiminoethano)- cyclopenta-[a]naphthalene-3a,8(1H)-diol 82

N-((2R,3aS,4R,9bS)-12-(cyclopropyl- methyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalen-2-yl)benzamide83

1-((2R,3aS,4R,9bS)-12-(cyclopropyl- methyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo-penta[a]naphthalen-2-yl)-3-phenylurea 84

(2R,3aS,4R,9bS)-12-(cyclopropyl- methyl)-3a,8-dihydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5- hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2- carboxamide 85

(2R,3aS,4R,9bS)-12-(cyclopropyl- methyl)-3a,8-dihydroxy-N-(3-morpholinopropyl)-1,2,3,3a,4,5- hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2- carboxamide 86

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(4-phenylpiperazin-1- yl)methanone 87

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(thiomorpholino)- methanone 88

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(4-(pyrrolidin-1- yl)piperidin-1-yl)methanone 89

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-3-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 90

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-4-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 91

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(3-morpholinopropyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 92

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-3-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 93

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 94

((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(1,1-dioxido- thiomorpholino)methanone

In another embodiment, Compounds of the Invention are compounds of TABLE2, and the pharmaceutically acceptable salts and solvates thereof.

TABLE 2 Compound No. Structure Chemical name  95

N-((2R,3aS,4R,9bR)-12-(cyclopropyl- methyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)- cyclopenta[a]naphthalen-2-yl)benzene-sulfonamide  96

((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(4-phenylpiperazin-1- yl)methanone  97

(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide 98

(2R,3aS,4R,9bS)-N-(2,4-dihydroxy- benzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b- (epiminoethano)cyclopenta[a]naphthalene-2-carboxamide  99

(2R,3aS,4R,9bS)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carboxamide 100

(2R,3aS,4R,9bS)-3a,8-dihydroxy-12- methyl-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide101

(2S,3aS,4R,9bS)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide102

(2S,3aS,4R,9bS)-3a,8-dihydroxy-N- isobutyl-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide103

(2R,3aS,4R,9bS)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide104

(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide105

(2R,3aS,4R,9bS)-N-benzyl-3a,8- dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide106

(2S,3aS,4R,9bS)-N-benzyl-3a,8- dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide107

(2S,3aS,4R,9bS)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide108

(2S,3aS,4R,9bS)-3a,8-dihydroxy-12- methyl-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide109

N-((2S,3aS,4R,9bR)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen- 2-yl)benzamide 110

N-((2R,3aS,4R,9bR)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen- 2-yl)benzamide 111

((2R,3aS,4R,9bS)-3a,8-dihydroxy-12- methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen- 2-yl)(morpholino)methanone 112

(2R,3aS,4R,9bS)-3a,8-dihydroxy-12- methyl-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 113

(2R,3aS,4R,9bS)-N-(2-(dimethylamino)-ethyl)-3a,8-dihydroxy-N,12-dimethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 114

(2R,3aS,4R,9bS)-3a,8-dihydroxy-N-(2-hydroxyethyl)-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide115

(2S,3aS,4R,9bS)-3a,8-dihydroxy-N-(2-hydroxyethyl)-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclo- penta[a]naphthalene-2-carboxamide116

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)- 3a-hydroxy-N²-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2,8- dicarboxamide 117

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)- 3a-hydroxy-N²-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2,8- dicarboxamide 118

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-N²-(2-morpholinoethyl)- 1,2,3,3a,4,5-hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2,8- dicarboxamide 119

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-N²-(2-morpholinoethyl)- 1,2,3,3a,4,5-hexahydro-4,9b-(epimino-ethano)cyclopenta[a]naphthalene-2,8- dicarboxamide 120

(2R,3aS,4R,9bS)-8-cyano-12- (cyclopropylmethyl)-3a-hydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 121

(2S,3aS,4R,9bS)-8-cyano-12- (cyclopropylmethyl)-3a-hydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 122

(2R,3aS,4R,9bS)-8-cyano-12- (cyclopropylmethyl)-3a-hydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 123

(2S,3aS,4R,9bS)-8-cyano-12- (cyclopropylmethyl)-3a-hydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 124

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,3-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 125

(2R,3aS,4R,9bS)-N-(3-chloro-2- methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 126

(2R,3aS,4R,9bS)-N-(3-chloro-4- methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 127

(2R,3aS,4R,9bS)-N-(2-chloro-4- hydroxybenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 128

(2R,3aS,4R,9bS)-N-(3-chloro-4- hydroxybenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 129

(2R,3aS,4R,9bS)-N-(4-chlorophenethyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 130

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)- N-(2,4-dichlorophenethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene- 2-carboxamide 131

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)- N-(3,4-dichlorophenethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene- 2-carboxamide 132

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalen-2-yl)(4-isopropylpiperazin- 1-yl)methanone 133

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(2-(piperidin-1- yl)ethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene- 2-carboxamide 134

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)-ethyl)-3a,8-dihydroxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carboxamide 135

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)-ethyl)-3a,8-dihydroxy-1,2,3,3a,4,5- hexahydro-4,9b-(epiminoethano)cyclo-penta[a]naphthalene-2-carboxamide 136

(2R,3aS,4R,9bS)-N-(4-chloro-2- fluorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 137

(2S,3aS,4R,9bS)-N-(3-chloro-4- methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 138

(2S,3aS,4R,9bS)-N-(3-chloro-2- methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro- 4,9b-(epiminoethano)cyclopenta-[a]naphthalene-2-carboxamide 139

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 140

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 141

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,3-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexabydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 142

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(3-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 143

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 144

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 145

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 146

(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 147

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 148

(2R,3aS,4R,9bS)-N-(2-chlorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 149

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(2-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 150

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 151

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,5-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide 152

(2R,3aS,4R,9bS)-N-(3-chlorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epimino- ethano)cyclopenta[a]naphthalene-2-carboxamide

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I, IA, and II-XV, wherein R¹ is —O-PG, wherein PG is ahydroxyl protecting group.

In another embodiment, Compounds of the Invention are compounds ofFormula I or IA, represented by Formula XVI:

wherein R², R³ and G are as defined for Formula I. Suitable andpreferable definitions for R², R³ and G are those described above forany of Formulae I, IA, and II-XV.

Suitable hydroxyl protecting groups for PG are well known and include,for example, any suitable hydroxyl protecting group disclosed in Wuts,P. G. M. & Greene, T. W., Greene's Protective Groups in OrganicSynthesis, 4rd Ed., pp. 16-430 (J. Wiley & Sons, 2007), hereinincorporated by reference in its entirety. The term “hydroxyl protectinggroup” as used herein refers to a group that blocks (i.e., protects) thehydroxy functionality while reactions are carried out on otherfunctional groups or parts of the molecule. Those skilled in the artwill be familiar with the selection, attachment, and cleavage ofprotecting groups and will appreciate that many different protectivegroups are known in the art, the suitability of one protective group oranother being dependent on the particular synthetic scheme planned.Suitable hydroxy protecting groups are generally able to be selectivelyintroduced and removed using mild reaction conditions that do notinterfere with other portions of the subject compounds. These protectinggroups can be introduced or removed at a convenient stage using methodsknown in the art. The chemical properties of such groups, methods fortheir introduction and removal are known in the art and can be found,for example, in Greene, T. W. and Wuts, P. G. M., above. Additionalhydroxyl protecting groups can be found, for example, in U.S. Pat. No.5,952,495, U.S. Patent Appl. Pub. No. 2008/0312411, WO 2006/035195, andWO 98/02033, which are herein incorporated by reference in theirentireties. Suitable hydroxyl protecting groups include themethoxymethyl, tetrahydropyranyl, tert-butyl, allyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl,benzoyl, benzyl (Bn), and p-methoxybenzyl group.

It will be apparent to a person of ordinary skill in the art in view ofthis disclosure that certain groups included in the definitions of —O-PGoverlap with the other definitions for R¹, such as methoxy, tert-butoxy,etc., and, thus, certain Compounds of the Invention having R¹ groupsthat include groups acting as hydroxyl protecting groups can bepharmaceutically active as described herein.

In one embodiment, the hydroxyl protecting group PG is selected from thegroup consisting of alkyl, arylalkyl, heterocyclo, (heterocyclo)alkyl,acyl, silyl, and carbonate, any of which are optionally substituted.

In another embodiment, the hydroxyl protecting group PG is an alkylgroup, typically an optionally substituted C₁₋₆ alkyl group, andsuitably unsubstituted methyl or tert-butyl.

In another embodiment, the hydroxyl protecting group PG is an arylalkylgroup. Suitable arylalkyl groups include, for example, an unsubstitutedbenzyl group, substituted benzyl groups, such as p-methoxybenzyl, andnaphthylmethyl.

In another embodiment, the hydroxyl protecting group PG is a heterocyclogroup, such as unsubstituted tetrahydropyranyl or optionally substitutedtetrahydropyranyl.

In another embodiment, the hydroxyl protecting group PG is a(heterocyclo)alkyl group. Suitable (heterocyclo)alkyl groups include,for example, 4-morpholinyl(C₁₋₄)alkyl groups, such as,2-(4-morpholinyl)ethyl.

In another embodiment, the hydroxyl protecting group PG is a silylgroup. The term “silyl” as employed herein refers to the group havingthe following structure:

wherein R¹⁷, R¹⁸, and R¹⁰ are each independently selected from the groupconsisting of alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl,any of which is optionally substituted. In one embodiment, the silylgroup is trimethyl silyl, tert-butyldimethyl silyl, tert-butyldiphenylsilyl, or tri-isopropyl silyl.

In another embodiment, the hydroxyl protecting group PG is an acylgroup. The term “acyl” as employed herein refers to the followingstructure:

wherein R²⁰ is alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl,any of which is optionally substituted. The acyl group can be, forexample, C₁₋₄ alkylcarbonyl (such as, for example, acetyl), arylcarbonyl(such as, for example, benzoyl), levulinoyl, or pivaloyl. In anotherembodiment, the acyl group is benzoyl.

In another embodiment, the hydroxyl protecting group is a carbonategroup. The term “carbonate” as employed herein refers to the followingstructure:

wherein R²¹ is alkyl, alkenyl, cycloalkyl, aryl, (cycloalkyl)alkyl, orarylalkyl, any of which is optionally substituted. Typically, R²¹ isC₁₋₁₀ alkyl (e.g., 2,4-dimethylpent-3-yl), C₂₋₆ alkenyl (e.g., ethenylor prop-2-enyl, i.e., allyl), C₃₋₁₂ cycloalkyl (e.g., adamantyl),phenyl, or benzyl. In one embodiment, the carbonate isbenzyloxycarbonyl.

The term “amine protecting group” as used herein refers to a group thatblocks (i.e., protects) the amine functionality while reactions arecarried out on other functional groups or parts of the molecule. Thoseskilled in the art will be familiar with the selection, attachment, andcleavage of amine protecting groups and will appreciate that manydifferent protective groups are known in the art, the suitability of oneprotective group or another being dependent on the particular syntheticscheme planned. Treatises on the subject are available for consultation,such as Wuts, P. G. M. & Greene, T. W., Greene's Protective Groups inOrganic Synthesis, 4rd Ed. (J. Wiley & Sons, 2007), herein incorporatedby reference in its entirety. Suitable amine protecting groups include—CH₂—O—(CH₂)₂—Si(CH₃)₃, carbobenzyloxy (Cbz), tert-butyloxycarbonyl(BOC), 9-fluorenylmethyloxycarbonyl (FMOC), benzoyl (Bz), acetyl (Ac),carbamate, tosyl (Ts), and benzyl (Bn) groups.

Optional substituents attached to aryl, phenyl and heteroaryl rings eachtake the place of a hydrogen atom that would otherwise be present in anyposition on the aryl, phenyl or heteroaryl rings.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chain and branched-chainC₁₋₁₀ alkyl groups. Typical C₁₋₁₀ alkyl groups include methyl (Me),ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,and n-decyl, isopropyl, sec-butyl, tert-butyl, iso-butyl, iso-pentyl,neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,1,3-dimethylheptyl, and 3,3-dimethylheptyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₁₋₆alkyl groups and branched chain C₃₋₆ alkyl groups. Typical C₁₋₆ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, iso-butyl, pentyl, 3-pentyl, hexyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₂₋₆alkyl groups and branched chain C₃₋₆ alkyl groups. Typical C₂₋₆ alkylgroups include ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, pentyl, 3-pentyl, hexyl among others. In one embodiment,useful alkyl groups are selected from straight chain C₁₋₄ alkyl groupsand branched chain C₃₋₄ alkyl groups. Typical C₁₋₄ alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, andiso-butyl.

Useful alkenyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl. TypicalC₂₋₆ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,sec-butenyl, pentenyl, and hexenyl. Typical C₂₋₄ alkenyl groups includeethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

Useful alkynyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl. TypicalC₂₋₆ alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,pentynyl, and hexynyl groups. Typical C₂₋₄ alkynyl groups includeethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, preferably any of the above-mentioned C₁₋₆ alkyl groups, andpreferably any of the above-mentioned C₁₋₄ alkyl groups, substituted byone or more fluorine, chlorine, bromine or iodine atoms (e.g.,fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethylgroups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, preferably any of the above-mentioned C₁₋₆ alkyl groups,and preferably any of the above-mentioned C₁₋₄ alkyl groups, substitutedby one or more hydroxy groups, such as monohydroxyalkyl anddihydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, hydroxypentyl, and hydroxyhexyl groups, and especiallyhydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,2-hydroxypropyl, 2-hydroxyprop-2-yl, 3-hydroxypropyl,2,3-dihydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl,2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl). In oneembodiment, the monohydroxyalkyl is monohydroxy(C₁₋₄ alkyl. In oneembodiment, the dihydroxyalkyl is dihydroxy(C₁₋₄ alkyl.

Useful cycloalkyl groups, as used by itself or as part of another group,are selected from saturated cyclic hydrocarbon groups containing 1, 2,or 3 rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e.,C₃-C₁₂ cycloalkyl) or the number of carbons designated. In oneembodiment, the cycloalkyl has one or two rings. In another embodiment,the cycloalkyl is a C₃-C₈ cycloalkyl. In another embodiment, thecycloalkyl is C₃₋₇ cycloalkyl. In another embodiment, the cycloalkyl isC₃₋₆ cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl,decalin, and adamantyl.

Useful cycloalkenyl groups, as used by itself or as part of anothergroup, are selected from partially unsaturated (i.e., containing one ortwo double bonds) cyclic hydrocarbon groups containing 1, 2, or 3 ringshaving 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C₄-C₁₂cycloalkenyl) or the number of carbons designated. In one embodiment,the cycloalkenyl has one or two rings. In another embodiment, thecycloalkenyl is a C₃-C₈ cycloalkenyl. In another embodiment, thecycloalkenyl is C₃₋₇ cycloalkenyl. In another embodiment, thecycloalkenyl is C₃₋₆ cycloalkenyl. In one embodiment, the cycloalkenylgroup contains one double bond. Exemplary cycloalkenyl groups containingone double bond include cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. In anotherembodiment, the cycloalkenyl group contains two double bonds.Preferably, the cycloalkenyl groups containing two double bonds have 5,6, 7, 8, 9, 10, 1, or 12 carbon atoms (i.e., C₅-C₁₂ cycloalkadienyl).Exemplary cycloalkenyl groups having two double bonds includecyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl,cyclononadienyl, and cyclodecadienyl.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy,iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, pentyloxy,hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy), preferably by oneof the C₁₋₆ alkyl groups, and more preferably by one of the C₁₋₄ alkylgroups.

Useful alkenyloxy groups include oxygen substituted by one of the C₂₋₆alkenyl groups, and preferably by one of the C₂₋₄ alkenyl groups,mentioned above (e.g., ethenyloxy, propenyloxy, isopropenyloxy,butenyloxy, sec-butenyloxy, pentenyloxy, and hexenyloxy).

Useful alkynyloxy groups include oxygen substituted by one of the C₂₋₆alkynyl groups, preferably by one of the C₂₋₄ alkynyl groups, mentionedabove (e.g., ethynyloxy, propynyloxy, butynyloxy, 2-butynyloxy,pentynyloxy, and hexynyloxy).

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted with any of the above-mentioned alkoxy groups (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, propoxymethyl,iso-propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups, and preferably one of the C₁₋₆ haloalkyl groups,mentioned above (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy,and 2,2,2-trifluoroethoxy).

The term “(cycloalkyl)alkyl” as used by itself or as part of anothergroup refers to any of the above-mentioned C₁₋₁₀ alkyl groups, andpreferably any of the above-mentioned C₁₋₆ alkyl groups, substitutedwith any of the above-mentioned cycloalkyl groups (e.g.,(cyclopropyl)methyl, 2-(cyclopropyl)ethyl, (cyclopropyl)propyl,(cyclobutyl)methyl, (cyclopentyl)methyl, and (cyclohexyl)methyl).

The term “(cycloalkenyl)alkyl” as used by itself or as part of anothergroup refers to any of the above-mentioned C₁₋₁₀ alkyl groups, andpreferably any of the above-mentioned C₁₋₆ alkyl groups, substitutedwith any of the above-mentioned cycloalkenyl groups (e.g.,(cyclobutenyl)methyl, 2-(cyclobutenyl)ethyl, (cyclobutenyl)propyl,(cyclopentenyl)methyl, (cyclohexenyl)methyl, and(cyclopentadienyl)methyl).

Useful aryl groups, as used by itself or as part of another group, areC₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄ aryl groups includephenyl (Ph), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl,biphenyl, biphenylenyl, and fluorenyl groups, more preferably phenyl,naphthyl, and biphenyl groups.

Useful aryloxy groups include oxygen substituted by one of the arylgroups mentioned above (e.g., phenoxy).

The term “arylalkyl” as used by itself or as part of another grouprefers to any of the above-mentioned C₁₋₁₀ alkyl groups, and preferablyany of the above-mentioned C₁₋₆ alkyl groups, substituted by any of theabove-mentioned aryl groups (e.g., benzyl and phenethyl).

Useful arylalkenyl groups include any of the above-mentioned C₂₋₆alkenyl groups substituted by any of the above-mentioned aryl groups(e.g., phenylethenyl).

Useful arylalkynyl groups include any of the above-mentioned C₂₋₆alkynyl groups substituted by any of the above-mentioned aryl groups(e.g., phenylethynyl).

Useful aralkyloxy or arylalkoxy groups include oxygen substituted by oneof the above-mentioned arylalkyl groups (e.g., benzyloxy).

Useful (arylalkoxy)carbonyl groups include a carbonyl group substitutedby any of the above-mentioned arylalkoxy groups (e.g.,(benzyloxy)carbonyl).

The term “heteroaryl” or “heteroaromatic” as employed herein by itselfor as part of another group refers to groups having 5 to 14 ring atoms,with 6, 10 or 14 π electrons shared in a cyclic array, and containingcarbon atoms and 1, 2, or 3 oxygen, nitrogen or sulfur heteroatoms, or 4nitrogen atoms. In one embodiment, the heteroaryl group is a 5- to10-membered heteroaryl group. Examples of heteroaryl groups includethienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl,benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl,xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl,furazanyl, and phenoxazinyl. Typical heteroaryl groups include thienyl(e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl),pyrrolyl (e.g., pyrrol-1-yl, 1H-pyrrol-2-yl and 1H-pyrrol-3-yl),imidazolyl (e.g., imidazol-1-yl, 1H-imidazol-2-yl and 1H-imidazol-4-yl),tetrazolyl (e.g., tetrazol-1-yl and tetrazol-5-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl). A 5-membered heteroaryl can contain up to 4 heteroatoms.A 6-membered heteroaryl can contain up to 3 heteroatoms. Each heteroatomis independently selected from nitrogen, oxygen and sulfur.

The term “heteroarylalkyl” as used by itself or as part of another grouprefers to any of the above-mentioned C₁₋₁₀ alkyl groups substituted byany of the above-mentioned heteroaryl groups (e.g., (thien-2-yl)methyl,2-furylmethyl, (pyrrol-1-yl)methyl, and 2-(1H-pyrrol-2-yl)ethyl).

Useful heteroarylalkoxy groups include oxygen substituted by one of theabove-mentioned heteroaryl groups.

Useful (heteroarylalkoxy)carbonyl groups include a carbonyl groupsubstituted by any of the above-mentioned heteroarylalkoxy groups.

The terms “heterocyclic” and “heterocyclo” as used by itself or as partof another group mean saturated or partially unsaturated 3-7 memberedmonocyclic, or 7-10 membered bicyclic ring system, which consist ofcarbon atoms and from one to four heteroatoms independently selectedfrom the group consisting of O, N, and S, wherein the nitrogen andsulfur heteroatoms can be optionally oxidized, the nitrogen can beoptionally quaternized, and including any bicyclic group in which any ofthe above-defined heterocyclic rings is fused to a benzene ring, andwherein the heterocyclic ring can be substituted on a carbon atom or ona nitrogen atom if the resulting compound is stable. In one embodiment,the 3- to 7-membered monocyclic heterocyclic ring is either a saturated,or unsaturated non-aromatic ring. A 3-membered heterocyclo can containup to 1 heteroatom, a 4-membered heterocyclo can contain up to 2heteroatoms, a 5-membered heterocyclo can contain up to 4 heteroatoms, a6-membered heterocyclo can contain up to 4 heteroatoms, and a 7-memberedheterocyclo can contain up to 5 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 3- to 7-memberedheterocyclo can be attached via a nitrogen or carbon atom. A 7- to10-membered bicyclic heterocyclo contains from 1 to 4 heteroatomsindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 7- to 10-memberedbicyclic heterocyclo can be attached via a nitrogen or carbon atom.Examples of the heterocyclic rings include, but are not limited to,pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl,oxazolidinyl, 2-oxooxazolidinyl, tetrahydrothienyl, imidazolidinyl,hexahydropyrimidinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andbenzodiazepines.

The term “(heterocyclo)alkyl” as used by itself or as part of anothergroup refers to any of the above-mentioned C₁₋₁₀ alkyl groups, andpreferably any of the above-mentioned C₁₋₆ alkyl groups, substituted byany of the above-mentioned heterocyclic groups (e.g.,(pyrrolidin-2-yl)methyl, (pyrrolidin-1-yl)methyl,(piperidin-1-yl)methyl, (morpholin-4-yl)methyl,(2-oxooxazolidin-4-yl)methyl, 2-(2-oxooxazolidin-4-yl)ethyl,(2-oxo-imidazolidin-1-yl)methyl, (2-oxo-imidazolidin-1-yl)ethyl, and(2-oxo-imidazolidin-1-yl)propyl).

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted with one or more amino group.

Useful alkylamino and dialkylamino groups are —NHR²² and —NR²²R²³,respectively, wherein R²² and R²³ are each independently selected from aC₁₋₁₀ alkyl group.

Useful (alkylamino)alkyl and (dialkylamino)alkyl groups include any ofthe above-mentioned C₁₋₁₀ alkyl groups, and preferably any of theabove-mentioned C₁₋₆ alkyl groups, substituted with any of theabove-mentioned alkylamino and dialkylamino groups, respectively.

As used herein, the term “aminocarbonyl” refers to —C(═O)NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(═O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful alkoxycarbonyl groups include a carbonyl group substituted by anyof the above-mentioned alkoxy groups (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, iso-butoxycarbonyl, sec-butoxycarbonyl, andpentyloxycarbonyl).

Useful (alkoxycarbonyl)alkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted with any of the above-mentioned alkoxycarbonylgroup.

Useful arylcarbonyl groups include a carbonyl group substituted by anyof the above-mentioned aryl groups (e.g., benzoyl).

Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted byone of the above-mentioned alkylcarbonyl groups.

Useful alkylcarbonylamino or acylamino groups include any of theabove-mentioned alkylcarbonyl groups attached to an amino nitrogen, suchas methylcarbonylamino.

As used herein, the term “carboxamido” refers to a radical of formula—C(═O)NR²⁴R²⁵, wherein R²⁴ and R²⁵ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary carboxamido groups include —CONH₂, —CON(H)CH₃, —CON(CH₃)₂, and—CON(H)Ph.

Useful (aminocarbonyl)alkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted with one or more of the above-mentionedaminocarbonyl groups.

Useful alkylaminocarbonyl and dialkylaminocarbonyl groups are any of theabove-mentioned carboxamido groups, where R²⁴ is H and R²⁵ is C₁₋₁₀alkyl or where R²⁴ and R²⁵ are each independently selected from a C₁₋₁₀alkyl group, respectively.

Useful (alkylaminocarbonyl)alkyl and (dialkylaminocarbonyl)alkyl groupsinclude any of the above-mentioned C₁₋₁₀ alkyl groups, and preferablyany of the above-mentioned C₁₋₆ alkyl groups, substituted with any ofthe above-mentioned alkylaminocarbonyl and dialkylaminocarbonyl groups,respectively.

As used herein, the term “sulfonamido” refers to a radical of formula—SO₂NR²⁶R²⁷, wherein R²⁶ and R²⁷ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, and—SO₂N(H)Ph.

As used herein, the term “thiol” refers to —SH.

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by —COOH.

As used herein, the terms “hydroxyl” or “hydroxy” refer to —OH.

As used herein, the term “cyano” refers to —CN.

As used herein, the term “nitro” refers to —NO₂.

As used herein, the term “ureido” refers to —NH—C(═O)—NH₂.

As used herein, the term “azido” refers to —N₃.

As used herein, the term “guanidino” refers to —NH—C(═NH)—NH₂.

Useful guanidinoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by —NH—C(═NH)—NH₂.

The term “ambient temperature” as used herein means the temperature ofthe surroundings. The ambient temperature indoors is the same as roomtemperature, which is from about 20° C. to about 25° C.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment. Typically, the term “about” includes therecited number ±10%. Thus, “about 10” means 9 to 11.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

The term “portion(s)” or the phrase “portion(s) thereof” as used hereinin connection with, for example, the phrases “the cycloalkyl,cycloalkenyl, heterocyclo, aryl and heteroaryl portions are optionallysubstituted” or “said cycloalkyl, cycloalkenyl, heterocyclo, aryl, andheteroaryl portions thereof are optionally substituted”, respectively,refers to the cyclic moieties s (i.e., cycloalkyl, cycloalkenyl,heterocyclo, aryl and heteroaryl), of groups such as, for example,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,(cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,and heteroarylalkyl.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, typically 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl,aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar(C₁₋₆)alkyloxy,carboxamido, sulfonamido, azido, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy, carboxy,aminocarbonyl, (═O), and mercapto(C₁₋₆)alkyl groups mentioned above.Preferred optional substituents include halo, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, halo(C₁₋₆)alkoxy, and amino.

Compounds of the Invention encompass all the salts of the disclosedcompounds of Formulae I, IA, and II-XVI. The present inventionpreferably includes all non-toxic pharmaceutically acceptable saltsthereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

Compounds of the Invention also encompass solvates of any of thedisclosed compounds of Formulae I, IA, and II-XVI. Solvates typically donot significantly alter the physiological activity or toxicity of thecompounds, and as such may function as pharmacological equivalents. Theterm “solvate” as used herein is a combination, physical associationand/or solvation of a compound of the present invention with a solventmolecule such as, e.g. a disolvate, monosolvate or hemisolvate, wherethe ratio of solvent molecule to compound of the present invention isabout 2:1, about 1:1 or about 1:2, respectively. This physicalassociation involves varying degrees of ionic and covalent bonding,including hydrogen bonding. In certain instances, the solvate can beisolated, such as when one or more solvent molecules are incorporatedinto the crystal lattice of a crystalline solid. Thus, “solvate”encompasses both solution-phase and isolatable solvates. Compounds ofthe Invention may be present as solvated forms with a pharmaceuticallyacceptable solvent, such as water, methanol, ethanol, and the like, andit is intended that the invention includes both solvated and unsolvatedforms of compounds of any of Formulae I, IA, and II-XVI. One type ofsolvate is a hydrate. A “hydrate” relates to a particular subgroup ofsolvates where the solvent molecule is water. Solvates typically canfunction as pharmacological equivalents. Preparation of solvates isknown in the art. See, for example, M. Caira et al., J. Pharmaceut.Sci., 93(3):601-611 (2004), which describes the preparation of solvatesof fluconazole with ethyl acetate and with water. Similar preparation ofsolvates, hemisolvates, hydrates, and the like are described by E. C.van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), andA. L. Bingham et al., Chem. Commun.: 603-604 (2001). A typical,non-limiting, process of preparing a solvate would involve dissolving acompound of any of Formulae I, IA, and II-XVI in a desired solvent(organic, water, or a mixture thereof) at temperatures above about 20°C. to about 25° C., then cooling the solution at a rate sufficient toform crystals, and isolating the crystals by known methods, e.g.,filtration. Analytical techniques such as infrared spectroscopy can beused to confirm the presence of the solvent in a crystal of the solvate.

Compounds of the Invention can be isotopically-labeled (i.e.,radio-labeled). Examples of isotopes that can be incorporated into thedisclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively, andpreferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeled Compounds of theInvention can be prepared by methods known in the art in view of thisdisclosure. For example, tritiated Compounds of the Invention can beprepared by introducing tritium into the particular compound bycatalytic dehalogenation with tritium. This method may include reactinga suitable halogen-substituted precursor of a Compound of the Inventionwith tritium gas in the presence of an appropriate catalyst such as Pd/Cin the presence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

Isotopically labeled Compounds of the Invention, as well as thepharmaceutically acceptable salts and solvates thereof, can be used asradioligands to test for the binding of compounds to an opioid receptor.For example, a radio-labeled Compound of the Invention can be used tocharacterize specific binding of a test or candidate compound to thereceptor. Binding assays utilizing such radio-labeled compounds canprovide an in vitro alternative to animal testing for the evaluation ofchemical structure-activity relationships. For example, the receptorassay may be performed at a fixed concentration of a radiolabeledCompound of the Invention and at increasing concentrations of a testcompound in a competition assay. In a non-limiting embodiment, thepresent invention provides a method for screening a candidate compoundfor the ability to bind to an opioid receptor, comprising a) introducinga fixed concentration of a radio-labeled Compound of the Invention tothe receptor under conditions that permit binding of the radio-labeledcompound to the receptor to form a complex; b) titrating the complexwith a candidate compound; and c) determining the binding of thecandidate compound to said receptor.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms, such as epimers. The present inventionis meant to encompass the uses of all such possible forms, as well astheir racemic and resolved forms and mixtures thereof. The individualenantiomers may be separated according to methods known to those ofordinary skill in the art in view of the present disclosure. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that they include both E and Z geometric isomers. All tautomersare intended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “epimer” refers to diastereomers that have oppositeconfiguration at only one of two or more tetrahedral streogenic centrespresent in the respective molecular entities.

The term “stereogenic center” is an atom, bearing groups such that aninterchanging of any two groups leads to a stereoisomer.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treating” or “treatment” refers to administering a therapy inan amount, manner, or mode effective to improve a condition, symptom, orparameter associated with a disorder or to prevent progression of adisorder, to either a statistically significant degree or to a degreedetectable to one skilled in the art. An effective amount, manner, ormode can vary depending on the subject and may be tailored to thepatient.

Open terms such as “include,” “including,” “contain,” “containing” andthe like mean “comprising.”

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to receptors and are only partly effective asagonists are defined as “partial agonists”. Compounds that bind to areceptor but produce no regulatory effect, but rather block the bindingof ligands to the receptor are defined as “antagonists”. (Ross andKenakin, “Ch. 2: Pharmacodynamics: Mechanisms of Drug Action and theRelationship Between Drug Concentration and Effect”, pp. 31-32, inGoodman & Gilman's the Pharmacological Basis of Therapeutics, 10^(th)Ed. (J. G. Hardman, L. E. Limbird and A. Goodman-Gilman eds., 2001)).

In certain embodiments, the Compound of the Invention is an agonist atone or more of the μ, δ and/or κ opioid receptors. In certainnon-limiting embodiments, the Compound of the Invention produces fewerside effects and/or less severe side effects than currently availableanalgesic opioid compounds when administered at doses producingequivalent levels of analgesia and/or anti-hyperalgesia. In certainembodiments, the Compound of the Invention is an agonist at ORL-1 opioidreceptor.

In certain embodiments, Compounds of the Invention can be used incombination with at least one other therapeutic agent. The othertherapeutic agent can be, but is not limited to, a μ-opioid agonist, anon-opioid analgesic, a non-steroidal anti-inflammatory agent, a Cox-IIinhibitor, an anti-emetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca²⁺-channel blocker, an anticancer agent, or amixture thereof.

Compounds of the Invention potently bind to the μ and/or κ and/or δand/or ORL-1 opioid receptors. Compounds of the Invention can bemodulators at the μ and/or κ and/or δ and/or ORL-1 opioid receptors, andtherefore Compounds of the Invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, Compounds of the Invention are antagonists of oneor more opioid receptors. In another embodiment, Compounds of theInvention are antagonists of the μ and/or κ opioid receptors.

In some embodiments, Compounds of the Invention are partial agonists ofone or more opioid receptors. In another embodiment, Compounds of theInvention are partial agonists of the μ and/or κ opioid receptors.

In another embodiment, Compounds of the Invention are agonists of one ormore opioid receptors. In another embodiment, Compounds of the Inventionare agonists of the μ and/or κ opioid receptors.

In some embodiments, Compounds of the Invention have both: (i)antagonist activity at the ORL-1 receptor; and (ii) agonist activity atone or more of the μ, δ and/or κ receptors. In another embodiment,Compounds of the Invention have both: (i) antagonist activity at theORL-1 receptor; and (ii) agonist activity at the μ receptor. In anotherembodiment, Compounds of the Invention have both: (i) antagonistactivity at the μ receptor; and (ii) agonist activity at the κ receptor.In another embodiment, Compounds of the Invention have: (i) antagonistactivity at the ORL-1 receptor; (ii) antagonist activity at the μreceptor; and (iii) agonist activity at the κ receptor. In anotherembodiment, Compounds of the Invention have: (i) antagonist activity atthe μ receptor; (ii) agonist activity at the κ receptor; and (iii)antagonist activity at the δ receptor.

Compounds of the Invention that are antagonists of the μ-opioid receptoror agonists of κ-opioid receptor, or both, can be used/administered totreat or ameliorate constipation. Compounds of the Invention that areagonists of μ-opioid receptor can be used/administered to treat orameliorate diarrhea.

Compounds of the Invention can be used to treat or prevent acute,chronic pain (which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain), or surgical pain. Examplesof pain that can be treated or prevented using a Compound of theInvention include, but are not limited to, cancer pain, neuropathicpain, labor pain, myocardial infarction pain, pancreatic pain, colicpain, post-operative pain, headache pain, muscle pain, arthritic pain,and pain associated with a periodontal disease, including gingivitis andperiodontitis.

Acute pain includes, but is not limited to, perioperative pain,postoperative pain, post-traumatic pain, acute disease related pain, andpain related to diagnostic procedures, orthopedic manipulations, andmyocardial infarction. Acute pain in the perioperative setting includespain because of pre-existing disease, the surgical procedure, e.g.,associated drains, chest or nasogastric tubes, or complications, or acombination of disease-related and procedure-related sources.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Compounds of the Invention can be used to treat or prevent painassociated with inflammation or with an inflammatory disease in apatient. Such pain can arise where there is an inflammation of the bodytissue which can be a local inflammatory response or a systemicinflammation. For example, a Compound of the Invention can be used totreat or prevent pain associated with inflammatory diseases including,but not limited to, organ transplant rejection; reoxygenation injuryresulting from organ transplantation (see Grupp et al., J. Mol, CellCardiol. 31:297-303 (1999)) including, but not limited to,transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases, such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung diseases, such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory diseasesof the eye, including corneal dystrophy, trachoma, onchocerciasis,uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory disease of the gum, including gingivitis and periodontitis;tuberculosis; leprosy; inflammatory diseases of the kidney, includinguremic complications, glomerulonephritis and nephrosis; inflammatorydisease of the skin, including sclerodermatitis, psoriasis and eczema;inflammatory diseases of the central nervous system, including chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimer's disease, infectiousmeningitis, encephalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis; autoimmune diseases, including Type I and Type II diabetesmellitus; diabetic complications, including, but not limited to,diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), gangrene of thefeet, atherosclerotic coronary arterial disease, peripheral arterialdisease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, jointproblems, and a skin or mucous membrane complication (such as aninfection, a shin spot, a candidal infection or necrobiosis lipoidicadiabeticorum), immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory disease of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andartherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. Compounds ofthe Invention can also be used to treat or prevent pain associated withinflammatory disease that can, for example, be a systemic inflammationof the body, exemplified by gram-positive or gram negative shock,hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent that is administered as a treatmentfor cancer.

Compounds of the Invention can be used to treat or prevent painassociated with nerve injury (i.e., neuropathic pain). Chronicneuropathic pain is a heterogenous disease state with an unclearetiology. In chronic pain, the pain can be mediated by multiplemechanisms. This type of pain generally arises from injury to theperipheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. The chronic pain is differentfrom acute pain in that chronic neuropathic pain patients suffer theabnormal pain sensations that can be described as spontaneous pain,continuous superficial burning and/or deep aching pain. The pain can beevoked by heat-, cold-, and mechano-hyperalgesia or by heat-, cold-, ormechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiences. Stroke (spinal or brain) and spinal cordinjury can also induce neuropathic pain. Cancer-related neuropathic painresults from tumor growth compression of adjacent nerves, brain, orspinal cord. In addition, cancer treatments, including chemotherapy andradiation therapy, can cause nerve injury. Neuropathic pain includes butis not limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

Compounds of the Invention can be used to treat or prevent painassociated with migraine including, but not limited to, migraine withoutaura (“common migraine”), migraine with aura (“classic migraine”),migraine without headache, basilar migraine, familial hemiplegicmigraine, migrainous infarction, and migraine with prolonged aura.

Compounds of the Invention can also be used as an agent to treat orprevent withdrawal from alcohol addiction or drug addiction; as an agentto treat or prevent addictive disorders; as an agent to treat a pruriticcondition; and in treating or ameliorating constipation and diarrhea.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I, IA, and II-XVI, or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for treating a disorder responsive to the modulation ofone or more opioids receptors (e.g., any of the disorders listed above)in a patient suffering from said disorder.

Furthermore, the present invention is directed to a method ofmodulating, in particular activating, one or more opioid receptors in apatient in need thereof, said method comprising administering to thepatient at least one compound represented by any of defined Formulae I,IA, and II-XVI, or a pharmaceutically acceptable salt or solvatethereof.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I, IA, and II-XVI, or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament, in particular a medicament for modulating, inparticular activating, one or more opioid receptors, in a patient inneed thereof.

Synthesis of Compounds

Compounds of the Invention can be prepared using methods known to thoseskilled in the art in view of this disclosure, or by illustrativemethods shown in the schemes below. For example, compounds of FormulaeI, IA, and II-XVI can be prepared as shown in the Schemes A-F below.Additional methods of synthesis are described and illustrated in theworking examples set forth below.

Compound B is prepared from Compound A by reaction with a suitablesulfonyl azide, such as 4-acetamidobenzenesulfonyl azide, in thepresence of a suitable base, such as DBU, in a suitable solvent such asACN. Compound B is converted to Compound C by reaction with a suitableamine, wherein R^(a) and R^(b) are as defined for R⁶ and R⁷, in thepresence of a suitable catalyst, such as Rh₂(OAc)₄, in a suitablesolvent, such as toluene. Compound C is hydrolized to Compound D bytreatment with a suitable acid, such as conc. HCl. Compound D isconverted to Compound F by first conversion to acid chloride E bytreatment with a suitable reagent, such as oxalyl chloride, in asuitable solvent, such as DCM, followed by reaction of Compound E withan excess of a suitable amine, where R^(e) and R^(d) are as defined forR⁶ and R⁷, in a suitable solvent, such as THF.

Compound G is converted to Compound H by treatment with a suitable acid,such as TFA, in a suitable solvent, such as DCM.

Compound H is converted to Compound I by reaction with a suitablereagent, such as (bis(trifluoroacetoxy)iodo)benzene, in a suitablesolvent, such as aq. ACN. Compound H can also be dehydrated to CompoundJ by treatment with a suitable reagent, such as TFAA, in the presence ofa suitable base, such as DIPEA, in a suitable solvent, such as THF.

Compound K can be converted to Compound L by hydrogenation over asuitable catalyst, such as Pd(OH)₂, in a suitable solvent, such as AcOH.Compound L can be converted to Compound M by alkylation with a suitablealkyl halide, triflate, tosylate, mesylate, etc. in the presence of asuitable base, such as DIPEA, in a suitable solvent, such as ACN.Compound L can also be converted to Compound M by reductive amminationwith the appropriate aldehyde/ketone in the presence of a suitablereducing agent, such as NaBH(OAc)₃, in a suitable solvent, such as DCM.In Scheme D, R^(e) can be, for example, an alkyl group optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, alkyl, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein saidaryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R⁴ groups.

Subsequent side chain modifications can be accomplished via appropriatefunctional group manipulations known to one skilled in the art.

The starting compounds having the formula

can be prepared, for example, as described in Hupp C. D., et al.,Tetrahedron Letters 51:2359-2361 (2010) and Ida Y., et al., Bioorganic &Medical Chemistry 20:949-961 (2012).

The starting compounds having the formula

can be prepared, for example, as described in Polazzi J. O. et al., J.Med. Chem. 23:174-179 (1980).

The opposite isomer of Compound A′, having the formula

can be prepared according methods described in the art, such as, forexample, in US 2009/0156818, US 2009/0156820, and Hupp C. D., et al.(supra). Accordingly, for example, Compound A′″, where R¹ is OMe and R²is cyclopropylmethyl, can be prepared as described in Scheme E startingfrom CAS#6080-33-7:

Further, Compounds of the Invention where R¹ is CN or aminocarbonyl canbe prepared, e.g., as shown in Scheme F below.

One of the hydroxyl groups in Compound B1 can be selectedly protected astriflate to yield Compound B2 through a reaction using a suitabletriflate reagent (such as, N-Phenyl-bis(trifluoromethanesulfonimide)) inthe presence of a suitable salt (such as, caesium carbonate) in asuitable solvent (such as, THF). The triflate group (TfO—) in CompoundB2 can then be converted to a nitrile (—CN) group by reacting CompoundB2 with a suitable cyanide salt (such as, zinc cyanide) in the presenceof a suitable catalyst, such as, PdCl₂(dppf) with zinc dust, in asuitable solvent (such as, DMF) to offer Compound B3, which can furtherbe converted to Compound B4 in a suitable catalyst (such as,hydrido(dimethylphosphinous acid-kP)[hydrogenbis(dimethyl-phosphinito-kP)]-platinum (II)) in a suitable solvent, suchas, 1:1 EtOH/H₂O.

Testing of Compounds In Vitro Assay Protocols

μ-Opioid Receptor Binding Assay Procedures:

Radioligand dose-displacement binding assays for μ-opioid receptors used0.3 nM [³H]-diprenorphine (Perkin Elmer, Shelton, Conn.), with 5 mgmembrane protein/well in a final volume of 500 μl binding buffer (10 mMMgCl₂, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were carriedout in the absence or presence of increasing concentrations of unlabelednaloxone. All reactions were conducted in 96-deep well polypropyleneplates for 2 hours at room temperature. Binding reactions wereterminated by rapid filtration onto 96-well Unifilter GF/C filter plates(Perkin Elmer, Shelton, Conn.), presoaked in 0.5% polyethylenimine usinga 96-well tissue harvester (Perkin Elmer, Shelton, Conn.) followed byperforming three filtration washes with 500 μl of ice-cold bindingbuffer. Filter plates were subsequently dried at 50° C. for 2-3 hours.BetaScint scintillation cocktail (Perkin Elmer, Shelton, Conn.) wasadded (50 μl/well), and plates were counted using a Packard Top-Countfor 1 min/well. The data were analyzed using the one-site competitioncurve fitting functions in GraphPad PRISM™ v. 3.0 or higher (San Diego,Calif.), or an in-house function for one-site competition curve-fitting.

μ-Opioid Receptor Binding Data:

Generally, the lower the K_(i) value, the more effective Compounds ofthe Invention will be at treating or preventing pain or anotherCondition. In certain embodiments, Compounds of the Invention exhibit aK_(i) (nM) of about 10,000 or less for binding to μ-opioid receptors.Typically, Compounds of the Invention exhibit a K_(i) (nM) of about 1000or less for binding to μ-opioid receptors. In one embodiment, Compoundsof the Invention exhibit a K_(i) (nM) of about 300 or less for bindingto μ-opioid receptors. In another embodiment, Compounds of the Inventionexhibit a K_(i) (nM) of about 100 or less for binding to μ-opioidreceptors. In another embodiment, Compounds of the Invention exhibit aK_(i) (nM) of about 10 or less for binding to μ-opioid receptors. Instill another embodiment, Compounds of the Invention exhibit a K_(i)(nM) of about 1 or less for binding to μ-opioid receptors. In stillanother embodiment, Compounds of the Invention exhibit a K_(i) (nM) ofabout 0.1 or less for binding to μ-opioid receptors.

μ-Opioid Receptor Functional Assay Procedures:

[³⁵S]GTPγS functional assays were conducted using freshly thawedμ-receptor membranes prepared in-house from a cell line expressingrecombinant μ opioid receptor in a HEK-293, CHO or U-2 OS cellbackground, or purchased from a commercial source (Perkin Elmer,Shelton, Conn.; or DiscovRx, Fremont, Calif.). Assay reactions wereprepared by sequentially adding the following reagents to binding buffer(100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice (finalconcentrations indicated): membrane protein (0.026 mg/mL), saponin (10mg/mL), GDP (3 mM) and [³⁵S]GTPγS (0.20 nM; Perkin Elmer, Shelton,Conn.). The prepared membrane solution (190 μl/well) was transferred to96-shallow well polypropylene plates containing 10 μl of 20×concentrated stock solutions of the agonist [D-Ala², N-methyl-Phe⁴Gly-ol⁵]-enkephalin (DAMGO) prepared in dimethyl sulfoxide (DMSO).Plates were incubated for 30 min at about 25° C. with shaking Reactionswere terminated by rapid filtration onto 96-well Unifilter GF/B filterplates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester(Perkin Elmer, Shelton, Conn.) followed by three filtration washes with200 μl of ice-cold wash buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4).Filter plates were subsequently dried at 50° C. for 2-3 hours. BetaScintscintillation cocktail (Perkin Elmer, Shelton, Conn.) was added (50μl/well) and plates were counted using a Packard Top-Count for 1min/well. Data were analyzed using the sigmoidal dose-response curvefitting functions in GraphPad PRISM v. 3.0, or an in-house function fornon-linear, sigmoidal dose-response curve-fitting. [³⁵S]GTPγS functionalassays can also be conducted using freshly thawed μ-receptor membranesprepared from a cell line expressing recombinant μ opioid receptor in aCHO-K1 cell background.

μ-Opioid Receptor Functional Data:

μ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a μ-opioid receptor. Typically,Compounds of the Invention exhibit a μ GTP EC₅₀ (nM) of about 5000 orless. In certain embodiments, Compounds of the Invention exhibit a μ GTPEC₅₀ (nM) of about 2000 or less; or about 1000 or less; or about 100 orless; or about 10 or less; or about 1 or less; or about 0.1 or less.

μ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by DAMGO, a standard μ agonist. Generally, the μGTP E_(max) (%) value measures the efficacy of a compound to treat orprevent pain or other Conditions. Typically, Compounds of the Inventionexhibit a μ GTP E_(max) (%) of greater than about 10%; or greater thanabout 20%. In certain embodiments, Compounds of the Invention exhibit aμ GTP Emax (%) of greater than about 50%; or greater than about 65%; orgreater than about 75%; or greater than about 85%; or greater than about100%.

κ-Opioid Receptor Binding Assay Procedures:

Membranes from HEK-293 cells, CHO cells or U-2 OS cells expressing therecombinant human kappa opioid receptor (κ) were prepared by lysingcells in ice cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4)(10 mL/10 cm dish) followed by homogenization with a tissuegrinder/Teflon pestle. Membranes from a cell line naturally expressingkappa opioid receptor can also be used. Membranes were collected bycentrifugation at 30,000×g for 15 min at 4° C. and pellets wereresuspended in hypotonic buffer to a final concentration of 1-3 mg/mL.Protein concentrations were determined using the BioRad protein assayreagent with bovine serum albumen as standard. Aliquots of κ receptormembranes were stored at −80° C.

Radioligand dose displacement assays used 0.4 nM [³H]-U69,593 (GEHealthcare, Piscataway, N.J.; 40 Ci/mmole) with 15 μg membrane protein(recombinant opioid receptor expressed in HEK 293 cells; in-house prep)in a final volume of 200 μl binding buffer (5% DMSO, 50 mM Trizma base,pH 7.4). Non-specific binding was determined in the presence of 10 μMunlabeled naloxone or U69,593. All reactions were performed in 96-wellpolypropylene plates for 1 hour at a temperature of about 25° C. Bindingreactions were terminated by rapid filtration onto 96-well UnifilterGF/C filter plates (Perkin Elmer, Shelton, Conn.) presoaked in 0.5%polyethylenimine (Sigma). Harvesting was performed using a 96-welltissue harvester (Perkin Elmer, Shelton, Conn.) followed by fivefiltration washes with 200 μl ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 1-2 hours. Fifty μl/wellscintillation cocktail (Perkin Elmer, Shelton, Conn.) was added andplates were counted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Binding Data:

In certain embodiments, Compounds of the Invention exhibit a K_(i) (nM)for κ receptors of about 10,000 or more (which, for purposes of thisinvention, is interpreted as having no binding to the κ receptors).Certain Compounds of the Invention exhibit a K_(i) (nM) of about 20,000or less for κ receptors. In certain embodiments, Compounds of theInvention exhibit a K_(i) (nM) of about 10,000 or less; or about 5000 orless; or about 1000 or less; or about 500 or less; or about 450 or less;or about 350 or less; or about 200 or less; or about 100 or less; orabout 50 or less; or about 10 or less; or about 1 or less; or about 0.1or less for κ receptors.

κ-Opioid Receptor Functional Assay Procedures:

Functional [³⁵S]GTPγS binding assays were conducted as follows. κ opioidreceptor membrane solution was prepared by sequentially adding finalconcentrations of 0.026 μg/μl κ membrane protein (in-house), 10 μg/mLsaponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl,10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution(190 μl/well) was transferred to 96-shallow well polypropylene platescontaining 10 μl of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at a temperature of about 25°C. with shaking. Reactions were terminated by rapid filtration onto96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.)using a 96-well tissue harvester (Packard) and followed by threefiltration washes with 200 μl ice-cold binding buffer (10 mM NaH₂PO₄, 10mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50° C. for2-3 hours. Fifty μl/well scintillation cocktail (Perkin Elmer, Shelton,Conn.) was added and plates were counted in a Packard Top-Count for 1min/well.

κ-Opioid Receptor Functional Data:

κ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a κ receptor. Certain Compounds ofthe Invention exhibit a κ GTP EC₅₀ (nM) of about 20,000 or less tostimulate κ opioid receptor function. In certain embodiments, Compoundsof the Invention exhibit a κ GTP EC₅₀ (nM) of about 10,000 or less; orabout 5000 or less; or about 2000 or less; or about 1500 or less; orabout 1000 or less; or about 600 or less; or about 100 or less; or about50 or less; or about 25 or less; or about 10 or less; or about 1 orless; or about 0.1 or less.

κ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by U69,593. Certain Compounds of the Inventionexhibit a κ GTP E_(max) (%) of greater than about 1%; or greater thanabout 5%; or greater than about 10%; or greater than about 20%. Incertain embodiments, Compounds of the Invention exhibit a κ GTP E_(max)(%) of greater than about 50%; or greater than about 75%; or greaterthan about 90%; or greater than about 100%.

δ-Opioid Receptor Binding Assay Procedures:

δ-Opioid Receptor Binding Assay Procedures were conducted as follows.Radioligand dose-displacement assays used 0.3 nM [³H]-Naltrindole(Perkin Elmer, Shelton, Conn.; 33.0 Ci/mmole) with 5 μg membrane protein(Perkin Elmer, Shelton, Conn.) in a final volume of 500 μl bindingbuffer (5 mM MgCl₂, 5% DMSO, 50 mM Trizma base, pH 7.4). Non-specificbinding was determined in the presence of 25 μM unlabeled naloxone. Allreactions were performed in 96-deep well polypropylene plates for 1 hourat a temperature of about 25° C. Binding reactions were terminated byrapid filtration onto 96-well Unifilter GF/C filter plates (PerkinElmer, Shelton, Conn.) presoaked in 0.5% polyethylenimine (Sigma).Harvesting was performed using a 96-well tissue harvester (Perkin Elmer,Shelton, Conn.) followed by five filtration washes with 500 μl ice-coldbinding buffer. Filter plates were subsequently dried at 50° C. for 1-2hours. Fifty μl/well scintillation cocktail (Perkin Elmer, Shelton,Conn.) was added and plates are counted in a Packard Top-Count for 1min/well.

δ-Opioid Receptor Binding Data:

In certain embodiments, Compounds of the Invention exhibit a K_(i) (nM)for δ receptors of about 10,000 or more (which, for the purposes of thisinvention, is interpreted as having no binding to the δ receptors).Certain Compounds of the Invention exhibit a K_(i) (nM) of about 20,000or less for δ receptors. In one embodiment, Compounds of the Inventionexhibit a Ki (nM) of about 10,000 or less; or of about 9000 or less forδ receptors. In another embodiment, Compounds of the Invention exhibit aK_(i) (nM) of about 7500 or less; or of about 6500 or less; or of about5000 or less; or of about 3000 or less; or of about 2500 or less for δreceptors. In another embodiment, Compounds of the Invention exhibit aK_(i) (nM) of about 1000 or less; or of about 500 or less; or of about350 or less; or of about 250 or less; or of about 100 or less; or ofabout 10 or less for δ receptors.

δ-Opioid Receptor Functional Assay Procedures:

Functional [³⁵S]GTPγS binding assays were conducted as follows. δ opioidreceptor membrane solution was prepared by sequentially adding finalconcentrations of 0.026 μg/μl δ membrane protein (Perkin Elmer, Shelton,Conn.), 10 μg/mL saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to bindingbuffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. Theprepared membrane solution (190 μl/well) was transferred to 96-shallowwell polypropylene plates containing 10 μl of 20× concentrated stocksolutions of agonist prepared in DMSO. Plates were incubated for 30 minat a temperature of about 25° C. with shaking Reactions were terminatedby rapid filtration onto 96-well Unifilter GF/B filter plates (PerkinElmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) andfollowed by three filtration washes with 200 μl ice-cold binding buffer(10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequentlydried at 50° C. for 1-2 hours. Fifty μl/well scintillation cocktail(Perkin Elmer, Shelton, Conn.) was added and plates were counted in aPackard Top-count for 1 min/well.

δ-Opioid Receptor Functional Data:

δ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a δ receptor. Certain Compounds ofthe Invention exhibit a δ GTP EC₅₀ (nM) of about 20,000 or less; orabout 10,000 or less. In certain embodiments, Compounds of the Inventionexhibit a δ GTP EC₅₀ (nM) of about 3500 or less; or of about 1000 orless; or of about 500 or less; or of about 100 or less; or of about 90or less; or of about 50 or less; or of about 25 or less; or of about 10or less.

δ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by met-enkephalin. Certain Compounds of theInvention exhibit a δ GTP E_(max) (%) of greater than about 1%; or ofgreater than about 5%; or of greater than about 10%. In one embodiment,Compounds of the Invention exhibit a δ GTP E_(max) (%) of greater thanabout 30%. In another embodiment, Compounds of the Invention exhibit a δGTP E_(max) (%) of greater than about 50%; or of greater than about 75%;or of greater than about 90%. In another embodiment, Compounds of theInvention exhibit a δ GTP E_(max) (%) of greater than about 100%.

ORL-1 Receptor Binding Assay Procedure:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like receptor (ORL-1) (Perkin Elmer, Shelton, Conn.) wasprepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with atissue grinder/Teflon pestle. Membranes were collected by centrifugationat 30,000×g for 15 min at 4° C. and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrationswere determined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes werestored at −80° C.

Radioligand binding assays (screening and dose-displacement) use 0.1 nM[³H]-nociceptin (Perkin Elmer, Shelton, Conn.; 87.7 Ci/mmole) with 12 μgmembrane protein in a final volume of 500 μl binding buffer (10 mMMgCl₂, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Non-specific bindingwas determined in the presence of 10 nM unlabeled nociceptin (AmericanPeptide Company). All reactions were performed in 96-deep wellpolypropylene plates for 1 h at room temperature. Binding reactions wereterminated by rapid filtration onto 96-well Unifilter GF/C filter plates(Perkin Elmer, Shelton, Conn.) presoaked in 0.5% polyethylenimine(Sigma). Harvesting was performed using a 96-well tissue harvester(Perkin Elmer, Shelton, Conn.) followed by three filtration washes with500 μl ice-cold binding buffer. Filter plates were subsequently dried at50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (PerkinElmer, Shelton, Conn.) was added and plates are counted in a PackardTop-Count for 1 min/well. The data from screening and dose-displacementexperiments were analyzed using Microsoft Excel and the curve fittingfunctions in GraphPad PRISM™, v. 3.0 or higher, respectively, or anin-house function for one-site competition curve-fitting.

ORL-1 Receptor Binding Data:

Certain Compounds of the Invention can have a K_(i) (nM) of about 5000or less. In one embodiment, certain Compounds of the Invention can havea K_(i) (nM) of about 1000 or less. In one embodiment, certain Compoundsof the Invention can have a K_(i) (nM) of about 500 or less. In otherembodiments, the Compounds of the Invention can have a K_(i) (nM) ofabout 300 or less; or of about 100 or less; or of about 50 or less; orof about 20 or less. In yet other embodiments, the Compounds of theInvention can have a K_(i) (nM) of about 10 or less; or of about 1 orless; or of about 0.1 or less.

ORL-1 Receptor Functional Assay Procedure:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like (ORL-1) (Perkin Elmer, Shelton, Conn.) can be prepared bylysing cells in ice-cold hypotonic buffer (2.5 mM Mg Cl₂, 50 mM HEPES,pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/Teflon pestle. Membranes are collected by centrifugation at30,000×g for 15 min at 4° C., and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrations aredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes are storedat −80° C.

Functional [³⁵S]GTPγS binding assays are conducted as follows. ORL-1membrane solution is prepared by sequentially adding finalconcentrations of 0.026 μg/μl ORL-1 membrane protein, 10 μg/ml saponin,3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190μl/well) is transferred to 96-shallow well polypropylene platescontaining 10 μl of 20× concentrated stock solutions ofagonist/nociceptin prepared in DMSO. Plates are incubated for 30 min atroom temperature with shaking. Reactions are terminated by rapidfiltration onto 96-well Unifilter GF/B filter plates (Perkin Elmer,Shelton, Conn.) using a 96-well tissue harvester (Packard) and followedby three filtration washes with 200 μl ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates are subsequently dried at50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (PerkinElmer, Shelton, Conn.) is added and plates are counted in a PackardTop-Count for 1 min/well. Data are analyzed using the sigmoidaldose-response curve fitting functions in GraphPad PRISM v. 3.0 orhigher, or an in-house function for non-linear, sigmoidal dose-responsecurve-fitting.

ORL-1 Receptor Functional Data:

ORL-1 GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at an ORL-1 receptor. In certainembodiments, the Compounds of the Invention that have a high bindingaffinity (i.e. low K_(i) value) can have an ORL-1 GTP EC₅₀ (nM) ofgreater than about 10,000 (i.e. will not stimulate at therapeuticconcentrations) In certain embodiments Compounds of the Invention canhave an ORL-1 GTP EC₅₀ (nM) of about 20,000 or less. In one embodiment,the Compounds of the Invention can have an ORL-1 GTP EC₅₀ (nM) of about10,000 or less; or of about 5000 or less; or of about 1000 or less. Instill other embodiments, the Compounds of the Invention can have anORL-1 GTP EC₅₀ (nM) of about 100 or less; or of about 10 or less; or ofabout 1 or less; or of about 0.1 or less.

ORL-1 GTP E_(max)% is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist. Incertain embodiments, Compounds of the Invention can have an ORL-1 GTPE_(max) of less than 10% (which, for the purposes of this invention, isinterpreted as having antagonist activity at ORL-1 receptors). CertainCompounds of the Invention can have an ORL-1 GTP E_(max) (%) of greaterthan 1%; or of greater than 5%; or of greater than 10%. In otherembodiments, Compounds of the Invention can have an ORL-1 GTP E_(max) ofgreater than 20%; or of greater than 50%; or of greater than 75%; or ofgreater than 88%; or of greater than 100%.

In Vivo Assays for Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a Compound ofthe Invention when food is removed for about 16 hours before dosing. Acontrol group acts as a comparison to rats treated with a Compound ofthe Invention. The control group is administered the carrier for theCompound of the Invention. The volume of carrier administered to thecontrol group is the same as the volume of carrier and Compound of theInvention administered to the test group.

Acute Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of acute pain, the rat tail flick can be used. Rats aregently restrained by hand and the tail exposed to a focused beam ofradiant heat at a point 5 cm from the tip using a tail flick unit (Model7360, commercially available from Ugo Basile of Italy). Tail flicklatencies are defined as the interval between the onset of the thermalstimulus and the flick of the tail. Animals not responding within 20seconds are removed from the tail flick unit and assigned a withdrawallatency of 20 seconds. Tail flick latencies are measured immediatelybefore (pre-treatment) and 1, 3, and 5 hours following administration ofa Compound of the Invention. Data are expressed as tail flick latency(s)and the percentage of the maximal possible effect (% MPE), i.e., 20seconds, is calculated as follows:

${\% \mspace{14mu} M\; P\; E} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \right\rbrack}{\left( {{20\mspace{14mu} s} - {{pre}\text{-}{administration}\mspace{14mu} {latency}}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

To assess the actions of a Compound of the Invention for the treatmentor prevention of acute pain, the rat hot plate test can also be used.Rats are tested using a hot plate apparatus consisting of a clearplexiglass cylinder with a heated metal floor maintained at atemperature of 48-52° C. (Model 7280, commercially available from UgoBasile of Italy). A rat is placed into the cylinder on the hot plateapparatus for a maximum duration of 30 s, or until it exhibits anocifensive behavior (behavioral endpoint), at which time it is removedfrom the hot plate, and the response latency recorded. Hot platelatencies are measured immediately before (pre-treatment) and 1, 3, and5 hours following administration of a Compound of the Invention. Thenocifensive behavioral endpoint is defined as any of the following: 1)paw withdrawal, either as a sustained lift or with shaking or licking;2) alternating foot lifting; 3) excape or attempted escape from thetesting device; or 4) vocalization. Data are expressed as responselatency(s) and the percentage of the maximal possible effect iscalculated as described above for the tail flick test. The hot platetest is described in G. Woolfe and A. D. MacDonald, J. Pharmacol. Exp.Ther. 80:300-307 (1944).

Inflammatory Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of inflammatory pain, the Freund's complete adjuvant(“FCA”) model of inflammatory pain can be used. FCA-induced inflammationof the rat hind paw is associated with the development of persistentinflammatory mechanical hyperalgesia and provides reliable prediction ofthe anti-hyperalgesic action of clinically useful analgesic drugs (L.Bartho et al., “Involvement of Capsaicin-sensitive Neurones inHyperalgesia and Enhanced Opioid Antinociception in Inflammation,”Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). Theleft hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. Prior to injection of FCA (baseline) and 24 hourpost injection, the animal is assessed for response to noxiousmechanical stimuli by determining the PWT, as described below. Rats arethen administered a single injection of 1, 3, or 10 mg/kg of either aCompound of the Invention; 30 mg/kg of a control drug selected fromCelebrex, indomethacin or naproxen; or carrier. Responses to noxiousmechanical stimuli are determined 1, 3, 5 and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack} \times 100}$

Neuropathic Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of neuropathic pain, either the Seltzer model or the Chungmodel can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration. Percentage reversal ofneuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theInvention. The animal can also be assessed for response to noxiousthermal stimuli or for tactile allodynia, as described below. The Chungmodel for neuropathic pain is described in S. H. Kim, “An ExperimentalModel for Peripheral Neuropathy Produced by Segmental Spinal NerveLigation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia:

The paw pressure assay can be used to assess mechanical hyperalgesia.For this assay, hind paw withdrawal thresholds (PWT) to a noxiousmechanical stimulus are determined using an analgesymeter (Model 7200,commercially available from Ugo Basile of Italy) as described in C.Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). The ratis gently restrained, its hindpaw is placed on a small round platform,and punctate pressure is applied to the dorsal surface of the hindpaw ina graded manner. The maximum weight that is applied to the hind paw isset at 250 g and the end point is taken as complete withdrawal of thepaw. PWT is determined once for each rat at each time point and eitheronly the affected (ipsilateral; same side as the injury) rear paw istested, or both the ipsilateral and contralateral (non-injured; oppositeto the injury) rear paw are tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:

The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulusapplied to the plantar surface of the hindpaw are determined using aplantar test apparatus (commercially available from Ugo Basile of Italy)following the technique described by K. Hargreaves et al., “A New andSensitive Method for Measuring Thermal Nociception in CutaneousHyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposure time is setat 32 seconds to avoid tissue damage and any directed paw withdrawalfrom the heat source is taken as the end point. Three latencies aredetermined at each time point and averaged. Either only the affected(ipsilateral) paw is tested, or both the ipsilateral and contralateral(non-injured) paw are tested.

Assessment of Tactile Allodynia:

To assess tactile allodynia, rats are placed in clear, plexiglasscompartments with a wire mesh floor and allowed to habituate for aperiod of at least 15 minutes. After habituation, a series of von Freymonofilaments are presented to the plantar surface of the affected(ipsilateral) foot of each rat. The series of von Frey monofilamentsconsists of six monofilaments of increasing diameter, with the smallestdiameter fiber presented first. Five trials are conducted with eachfilament with each trial separated by approximately 2 minutes. Eachpresentation lasts for a period of 4-8 seconds or until a nociceptivewithdrawal behavior is observed. Flinching, paw withdrawal or licking ofthe paw are considered nociceptive behavioral responses.

Assessment of Respiratory Depression:

To assess respiratory depression, rats can be prepared by implanting afemoral artery cannula via which blood samples are taken. Blood samplesare taken prior to drug administration, then 1, 3, 5 and 24 hourspost-treatment. Blood samples are processed using an arterial blood gasanalyzer (e.g., IDEXX VetStat with Respiratory/Blood Gas testcartridges). Comparable devices are a standard tool for blood gasanalysis (e.g., D. Torbati et al., Intensive Care Med. (26): 585-591(2000).

Assessment of Gastric Motility:

Animals are treated with vehicle, reference compound or test article byoral gavage at a volume of 10 mL/kg. At one hour post-dose, all animalsare treated with charcoal meal solution (5% non-activated charcoalpowder in a solution of 1% carboxymethylcellulose in water) at a volumeof 10 mL/kg. At two hours post-dose (one hour post-charcoal), animalsare sacrificed by carbon dioxide inhalation or isoflurane overdose andthe transit of charcoal meal identified. The stomach and small intestineare removed carefully and each placed on a saline-soaked absorbentsurface. The distance between the pylorus and the furthest progressionof charcoal meal is measured and compared to the distance between thepylorus and the ileocecal junction. The charcoal meal transit isexpressed as a percentage of small intestinal length traveled.

Pharmaceutical Compositions

Due to their activity, the Compounds of the Invention are advantageouslyuseful in human and veterinary medicine. As described above, theCompounds of the Invention are useful for treating or preventing aCondition in a patient in need thereof. The Compounds of the Inventioncan be administered to any patient requiring modulation of the opioidreceptors. The term “patient” as used herein refers to any animal thatmay experience the beneficial effects of a Compound of the Invention.Foremost such animals are mammals, e.g., humans and companion animals,although the invention is not intended to be so limited.

When administered to a patient, a Compound of the Invention can beadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. A Compound of theInvention can be administered by any appropriate route, as determined bythe medical practitioner. Methods of administration may includeintradermal, intramuscular, intraperitoneal, parenteral, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, buccal,intracerebral, intravaginal, transdermal, transmucosal, rectal, byinhalation, or topical (particularly to the ears, nose, eyes, or skin).Delivery can be either local or systemic. In certain embodiments,administration will result in the release of a Compound of the Inventioninto the bloodstream.

Pharmaceutical compositions of the invention can take the form ofsolutions, suspensions, emulsions, tablets, pills, pellets, powders,multi-particulates, capsules, capsules containing liquids, capsulescontaining powders, capsules containing multi-particulates, lozenges,sustained-release formulations, suppositories, transdermal patches,transmucosal films, sub-lingual tablets or tabs, aerosols, sprays, orany other form suitable for use. In one embodiment, the composition isin the form of a tablet. In another embodiment, the composition is inthe form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical excipients are described inRemington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed.,19th ed. 1995), incorporated herein by reference.

Pharmaceutical compositions of the invention preferably comprise asuitable amount of a pharmaceutically acceptable excipient so as toprovide the form for proper administration to the patient. Such apharmaceutical excipient can be a diluent, suspending agent,solubilizer, binder, disintegrant, preservative, coloring agent,lubricant, and the like. The pharmaceutical excipient can be a liquid,such as water or an oil, including those of petroleum, animal,vegetable, or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil, and the like. The pharmaceutical excipient can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipient is sterile whenadministered to a patient. Water is a particularly useful excipient whena Compound of the Invention is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid excipients, particularly for injectable solutions.Suitable pharmaceutical excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. The inventioncompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986).

In certain embodiments, the Compounds of the Invention are formulatedfor oral administration. A Compound of the Invention to be orallydelivered can be in the form of tablets, capsules, gelcaps, caplets,lozenges, aqueous or oily solutions, suspensions, granules, powders,emulsions, syrups, or elixirs, for example. When a Compound of theInvention is incorporated into oral tablets, such tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, multiply compressed or multiply layered.

An orally administered Compound of the Invention can contain one or moreadditional agents such as, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,and stabilizers, to provide stable, pharmaceutically palatable dosageforms. Techniques and compositions for making solid oral dosage formsare described in Pharmaceutical Dosage Forms: Tablets (Lieberman,Lachman and Schwartz, eds., 2nd ed.) published by Marcel Dekker, Inc.Techniques and compositions for making tablets (compressed and molded),capsules (hard and soft gelatin) and pills are also described inRemington's Pharmaceutical Sciences 1553-1593 (Arthur Osol, ed., 16^(th)ed., Mack Publishing, Easton, Pa. 1980). Liquid oral dosage formsinclude aqueous and nonaqueous solutions, emulsions, suspensions, andsolutions and/or suspensions reconstituted from non-effervescentgranules, optionally containing one or more suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, coloring agents, flavoring agents, and the like. Techniquesand compositions for making liquid oral dosage forms are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger andBanker, eds.) published by Marcel Dekker, Inc.

When a Compound of the Invention is formulated for parenteraladministration by injection (e.g., continuous infusion or bolusinjection), the formulation can be in the form of a suspension,solution, or emulsion in an oily or aqueous vehicle, and suchformulations can further comprise pharmaceutically necessary additivessuch as one or more stabilizing agents, suspending agents, dispersingagents, and the like. When a Compound of the Invention is to be injectedparenterally, it can be, e.g., in the form of an isotonic sterilesolution. A Compound of the Invention can also be in the form of apowder for reconstitution as an injectable formulation.

In certain embodiments, a Compound of the Invention is formulated into apharmaceutical composition for intravenous administration. Typically,such compositions comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent. ACompound of the Invention for intravenous administration can optionallyinclude a local anesthetic such as benzocaine or prilocaine to lessenpain at the site of the injection. Generally, the ingredients aresupplied either separately or mixed together in unit dosage form, forexample, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampule or sachette indicatingthe quantity of active agent. Where a Compound of the Invention is to beadministered by infusion, it can be dispensed, for example, with aninfusion bottle containing sterile pharmaceutical grade water or saline.Where a Compound of the Invention is administered by injection, anampule of sterile water for injection or saline can be provided so thatthe ingredients can be mixed prior to administration.

When a Compound of the Invention is to be administered by inhalation, itcan be formulated into a dry aerosol, or an aqueous or partially aqueoussolution.

In another embodiment, a Compound of the Invention can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); and Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer 317-327 and 353-365 (1989)).

In certain embodiments, a Compound of the Invention is administeredlocally. This can be achieved, for example, by local infusion duringsurgery, topical application, e.g., in conjunction with a wound dressingafter surgery, by injection, by means of a catheter, by means of asuppository or enema, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, a Compound of the Invention can be delivered inan immediate release form. In other embodiments, a Compound of theInvention can be delivered in a controlled-release system orsustained-release system. Controlled- or sustained-releasepharmaceutical compositions can have a common goal of improving drugtherapy over the results achieved by their non-controlled ornon-sustained-release counterparts. In one embodiment, a controlled- orsustained-release composition comprises a minimal amount of a Compoundof the Invention to treat or prevent the Condition (or a symptomthereof) in a minimum amount of time. Advantages of controlled- orsustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased compliance. In addition,controlled- or sustained-release compositions can favorably affect thetime of onset of action or other characteristics, such as blood levelsof the Compound of the Invention, and can thus reduce the occurrence ofadverse side effects.

Controlled- or sustained-release compositions can initially immediatelyrelease an amount of a Compound of the Invention that promptly producesthe desired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the Compound of the Invention tomaintain a level of therapeutic or prophylactic effect over an extendedperiod of time. To maintain a constant level of the Compound of theInvention in the body, the Compound of the Invention can be releasedfrom the dosage form at a rate that will replace the amount of Compoundof the Invention being metabolized and excreted from the body.Controlled- or sustained-release of an active ingredient can bestimulated by various conditions, including but not limited to, changesin pH, changes in temperature, concentration or availability of enzymes,concentration or availability of water, or other physiologicalconditions or compounds.

Controlled-release and sustained-release means for use according to thepresent invention may be selected from those known in the art. Examplesinclude, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and5,733,566, each of which is incorporated herein by reference. Suchdosage forms can be used to provide controlled- or sustained-release ofone or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, multiparticulates,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled- orsustained-release formulations known in the art, including thosedescribed herein, can be readily selected for use with the activeingredients of the invention in view of this disclosure. See alsoGoodson, “Dental Applications” (pp. 115-138) in Medical Applications ofControlled Release, Vol. 2, Applications and Evaluation, R. S. Langerand D. L. Wise eds., CRC Press (1984). Other controlled- orsustained-release systems that are discussed in the review by Langer,Science 249:1527-1533 (1990) can be selected for use according to thepresent invention. In one embodiment, a pump can be used (Langer,Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201(1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release(Langer and Wise eds., 1974); Controlled Drug Bioavailability, DrugProduct Design and Performance (Smolen and Ball eds., 1984); Ranger andPeppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)). In yet anotherembodiment, a controlled- or sustained-release system can be placed inproximity of a target of a Compound of the Invention, e.g., the spinalcolumn, brain, or gastrointestinal tract, thus requiring only a fractionof the systemic dose.

When in tablet or pill form, a pharmaceutical composition of theinvention can be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

Pharmaceutical compositions of the invention include single unit dosageforms suitable for oral administration such as, but not limited to,tablets, capsules, gelcaps, and caplets that are adapted for controlled-or sustained-release.

The amount of the Compound of the Invention that is effective for thetreatment or prevention of a condition can be determined by standardclinical techniques. In addition, in vitro and/or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on, e.g., the route ofadministration and the extent of the Condition to be treated, and can bedecided according to the judgment of a practitioner and/or eachpatient's circumstances. Variations in dosing may occur depending upontypical factors such as the weight, age, gender and physical condition(e.g., hepatic and renal function) of the patient being treated, theaffliction to be treated, the severity of the symptoms, the frequency ofthe dosage interval, the presence of any deleterious side-effects, andthe particular compound utilized, among other things.

Suitable effective dosage amounts can range from about 0.01 mg/kg ofbody weight to about 3000 mg/kg of body weight of the patient per day,although they are typically from about 0.01 mg/kg of body weight toabout 2500 mg/kg of body weight of the patient per day or from about0.01 mg/kg of body weight to about 1000 mg/kg of body weight of thepatient per day. In one embodiment, the effective dosage amount is about100 mg/kg of body weight of the patient per day or less. In anotherembodiment, the effective dosage amount ranges from about 0.01 mg/kg ofbody weight to about 100 mg/kg of body weight of the patient per day ofa Compound of the Invention, in another embodiment, about 0.02 mg/kg ofbody weight to about 50 mg/kg of body weight of the patient per day, andin another embodiment, about 0.025 mg/kg of body weight to about 20mg/kg of body weight of the patient per day.

Administration can be as a single dose or as a divided dose. In oneembodiment, an effective dosage amount is administered about every 24hours until the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 hours until the Conditionis abated. In another embodiment, an effective dosage amount isadministered about every 8 hours until the Condition is abated. Inanother embodiment, an effective dosage amount is administered aboutevery 6 hours until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 4 hours until theCondition is abated. The effective dosage amounts described herein referto total amounts administered; that is, if more than one Compound of theInvention is administered, the effective dosage amounts correspond tothe total amount administered.

Where a cell capable of expressing the t-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the μ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the δ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the δ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the κ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the κ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁴ mol/L, or from about10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁶mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of a solution orsuspension of the Compound of the Invention in a pharmaceuticallyacceptable carrier or excipient. In one embodiment, the volume ofsolution or suspension comprising the Compound of the Invention can befrom about 0.01 μL to about 1 mL. In another embodiment, the volume ofsolution or suspension can be about 200 μL.

Where a cell capable of expressing the ORL-1 receptor is contacted witha Compound of the Invention in vitro, the amount effective forinhibiting or activating the ORL-1 receptor function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁴ mol/L, or from about10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁶mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of a solution orsuspension of the compound in a pharmaceutically acceptable carrier orexcipient. In one embodiment, the volume of solution or suspensioncomprising the Compound of the Invention can be from about 0.01 μL toabout 1 mL. In another embodiment, the volume of solution or suspensioncan be about 200 μL.

Compounds of the Invention can be assayed in vitro or in vivo for thedesired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.Certain Compounds of the Invention are expected to have an ED₅₀ fortreating inflammatory pain ranging from about 0.5 mg/kg to about 20mg/kg. Certain Compounds of the Invention are expected to producesignificant analgesia and/or anti-hyperalgesia at doses that do notinduce respiratory depression. In contrast, oxygen tension, oxygensaturation and pH are significantly decreased, while carbon dioxide issignificantly increased, in blood samples from rats given effectivedoses of conventional opioids, such as morphine.

According to the present invention, methods for treating or preventing aCondition in apatient in need thereof can further compriseco-administering to the patient an effective amount of a secondtherapeutic agent in addition to a Compound of the Invention (i.e., afirst therapeutic agent). An effective amount of the second therapeuticagent can be known or determinable by a medical practitioner in view ofthis disclosure and published clinical studies. In one embodiment of theinvention, where a second therapeutic agent is administered to a patientfor treatment of a Condition (e.g., pain), the minimal effective amountof the Compound of the Invention (i.e., the first therapeutic agent)will be less than its minimal effective amount would be in circumstanceswhere the second therapeutic agent is not administered. In thisembodiment, the Compound of the Invention and the second therapeuticagent can act either additively or synergistically to treat or prevent aCondition. Alternatively, the second therapeutic agent may be used totreat or prevent a disorder that is different from the Condition forwhich the first therapeutic agent is being administered, and whichdisorder may or may not be a Condition as defined hereinabove. In oneembodiment, a Compound of the Invention is administered concurrentlywith a second therapeutic agent as a single composition comprising aneffective amount of a Compound of the Invention and an effective amountof the second therapeutic agent. Alternatively, a composition comprisingan effective amount of a Compound of the Invention and a secondcomposition comprising an effective amount of the second therapeuticagent are concurrently administered. In another embodiment, an effectiveamount of a Compound of the Invention is administered prior orsubsequent to administration of an effective amount of the secondtherapeutic agent. In this embodiment, the Compound of the Invention isadministered while the second therapeutic agent exerts its therapeuticeffect, or the second therapeutic agent is administered while theCompound of the Invention exerts its therapeutic effect for treating orpreventing a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-IA inhibitor, a 5-lipoxygenaseinhibitor, an anti-emetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca²⁺-channel blocker, an anti-cancer agent, an agentfor treating or preventing UI, an agent for treating or preventinganxiety, an agent for treating or preventing a memory disorder, an agentfor treating or preventing obesity, an agent for treating or preventingconstipation, an agent for treating or preventing cough, an agent fortreating or preventing diarrhea, an agent for treating or preventinghigh blood pressure, an agent for treating or preventing epilepsy, anagent for treating or preventing anorexia/cachexia, an agent fortreating or preventing drug abuse, an agent for treating or preventingan ulcer, an agent for treating or preventing IBD, an agent for treatingor preventing IBS, an agent for treating or preventing addictivedisorder, an agent for treating or preventing Parkinson's disease andparkinsonism, an agent for treating or preventing a stroke, an agent fortreating or preventing a seizure, an agent for treating or preventing apruritic condition, an agent for treating or preventing psychosis, anagent for treating or preventing Huntington's chorea, an agent fortreating or preventing ALS, an agent for treating or preventing acognitive disorder, an agent for treating or preventing a migraine, anagent for treating, preventing or inhibiting vomiting, an agent fortreating or preventing dyskinesia, an agent for treating or preventingdepression, or any mixture thereof.

A composition of the invention is prepared by a method comprisingadmixing a Compound of the Invention with a pharmaceutically acceptablecarrier or excipient. Admixing can be accomplished using methods knownfor admixing a compound (or derivative) and a pharmaceuticallyacceptable carrier or excipient. In one embodiment, the Compound of theInvention is present in the composition in an effective amount.

The present invention also relates to a kit, comprising a sterilecontainer containing an effective amount of a Compound of the Inventionand instructions for therapeutic use.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES

The following abbreviations are used:

ACN acetonitrile

AcOH acetic acid

aq. aqueous

atm atmosphere(s)

Bn benzyl

° C. degrees Celcius

conc. concentrated

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE dichloroethane

DCM dichloromethane

DIPEA diisopropylethylamine

DME 1,2-dimethoxyethane

DMF dimethylformamide

DMSO dimethylsulfoxide

Et₂O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

h hour(s)

HPLC high pressure liquid chromatography

i-PrOH iso-propanol

MeOH methanol

min minute(s)

MPLC medium pressure liquid chromatography

psi pounds per square inch

RT room temperature

satd. saturated

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

Example 1

DIPEA (13.3 mL, 76 mmol) was added to Compound 1 (27.4 g, 72.5 mmol) inAc₂O (68.4 mL, 725 mmol) and the solution was heated at 120° C. for 2 h.The reaction mixture was diluted with EtOAc, washed with two portions ofsatd. aq. NaHCO₃, dried over Na₂SO₄, and concentrated. ACN (300 mL) and4-acetamidobenzenesulfonyl azide (34.8 g, 145 mmol) were added, followedby DBU (32.8 mL, 218 mmol) at 0° C. The reaction was allowed to warm toRT over 18 h and concentrated. EtOAc was added, washed with two portionsof 1M aq. NaOH, dried over Na₂SO₄ and concentrated. The resulting brownsolid was triturated with acetone, filtered, and carried on withoutfurther purification to yield 17.28 g of Compound 2 as a yellow solid.LC/MS, m/z=410 [M+H]⁺ (Calc: 409).

The starting Compound 1 can be prepared as described in, for example,Hupp C. D., et al., Tetrahedron Letters 51:2359-2361 (2010).

Example 2(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2-guanidinoethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(6)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(4-guanidinobutyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(7)

(a) A solution of Compound 2 (0.5 g, 1.2 mmol) in 3 mL DCE was addedslowly to tert-butyl (2-aminoethyl)carbamate (0.21 mL, 1.3 mmol) andRh₂(OAc)₄ (27 mg, 0.6 mmol) in 2 mL toluene at 80° C. The solution washeated at reflux for 21 h, adding 2 mL toluene after 4 h, andconcentrated. The resulting material was purified by MPLC (0-8%MeOH/DCM) to yield Compound 3 (mixture of diastereomers) as a brown oil.

(b) DCM (10 mL) was added to Compound 3. A 1M solution of BBr₃ in DCM(6.1 mL, 6.1 mmol) was added at 0° C. and the solution stirred at 0° C.for 30 min. The reaction was quenched with MeOH followed by 7M NH₃/MeOHand concentrated. A 25% MeOH/DCM solution was added to the resultingmaterial, the solid removed by filtration, and the filtrate purified byMPLC (0-20% (10% NH₄OH/MeOH)/DCM) to yield 350 mg of Compound 4 (mixtureof diastereomers) as a brown oil. MeOH (5 mL) was added followed by 5drops of AcOH and the resulting solution heated at reflux for 16 h.Concentration led to Compound 5 (mixture of diastereomers) which wascarried on without further purification.

(c) DIPEA (0.419 mL, 2.4 mmol) was added to a solution of Compound 5(308 mg, 0.8 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (141mg, 0.96 mmol) in 4 mL DMF. The reaction mixture was stirred at 80° C.for 16 h, concentrated, and triturated with DCM. The resulting solid waspurified by preparatory HPLC [0-40% ACN/H₂O (0.01% TFA)] to yieldCompound 6 as its TFA salt.

Compound 6 TFA salt: ¹H NMR (MeOH-d₄) δ: 7.91 (br. s., 1H), 6.93 (d,J=8.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.56 (dd, J=8.1, 2.4 Hz, 1H),4.12 (d, J=4.6 Hz, 1H), 2.89-3.30 (m, 9H), 2.80 (dd, J=13.5, 7.6 Hz,1H), 2.58 (dd, J=13.2, 2.2 Hz, 1H), 2.31-2.48 (m, 3H), 2.14 (dd, J=13.4,8.4 Hz, 1H), 1.86 (dd, J=13.5, 8.7 Hz, 1H), 1.39-1.54 (m, 1H), 0.95-1.08(m, 1H), 0.68-0.79 (m, 1H), 0.58-0.68 (m, 1H), 0.34-0.46 (m, 2H); LC/MS,m/z=428 [M+H]⁺ (Calc: 427).

(d) Compound 7 TFA salt was prepared in an analogous fashion fromCompound 2 and tert-butyl (4-aminobutyl)carbamate:

Compound 7 TFA salt: ¹H NMR (MeOH-d₄) δ: 7.62-7.69 (m, 1H), 6.93 (d,J=8.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.56 (dd, J=8.4, 2.4 Hz, 1H),4.11 (d, J=4.6 Hz, 1H), 3.19-3.31 (m, 3H), 2.88-3.17 (m, 6H), 2.79 (dd,J=13.4, 7.7 Hz, 1H), 2.56 (dd, J=13.1, 2.5 Hz, 1H), 2.31-2.47 (m, 3H),2.10 (dd, J=13.4, 8.6 Hz, 1H), 1.86 (dd, J=13.5, 8.7 Hz, 1H), 1.47 (d,J=8.8 Hz, 1H), 1.28-1.42 (m, 4H), 0.95-1.08 (m, 1H), 0.69-0.78 (m, 1H),0.60-0.68 (m, 1H), 0.35-0.46 (m, 2H).

Example 3(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(11)

Rh₂(OAc)₄ (62 mg, 0.14 mmol) was added to a solution of Compound 2 (5.79g, 14.1 mmol) and 2,4-dimethoxybenzylamine (2.84 g, 17.0 mmol) in 75 mLtoluene. The solution was heated at reflux for 17 h and concentrated toyield Compound 8 as a mixture of diastereomers. MeOH (34 mL) was addedfollowed by 2.5M aq. NaOH (17 mL, 42.4 mmol). The solution was heated at80° C. for 3 h. MeOH was removed under vacuum, satd. aq. NaHCO₃ wasadded and the aqueous layer washed with two portions of DCM. Thecombined organic layers were dried over Na₂SO₄ and concentrated to yieldCompound 9 (mixture of diastereomers) as a brown foam. DCM (25 mL) wasadded followed by TFA (25 mL) and the solution stirred at RT for 2 h. Anadditional 25 mL aliquot of TFA was added and the solution stirred at RTfor 17 h. An additional 30 mL aliquot of 1:1 DCM:TFA was added and thesolution stirred at RT for 8 h and concentrated. DCM was added, washedwith two portions of 10% aq. NH₄OH, one portion of brine, dried overNa₂SO₄, and concentrated. The resulting material was purified by MPLC(0-20% MeOH/DCM) to yield 1.57 g of Compound 10 and 2.54 g of Compound11. Compound 11 was purified by preparatory HPLC [0-60% ACN/H₂O (0.01%TFA)] and isolated as its TFA salt.

Compound 11 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.73 (br. s, 1H), 7.06 (d,J=8.6 Hz, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.77 (dd, J=8.4, 2.6 Hz, 1H),6.61 (br. s., 1H), 5.85 (s, 1H), 4.07 (d, J=4.6 Hz, 1H), 3.24-3.38 (m,2H), 3.10-3.23 (m, 1H), 2.93-3.08 (m, 2H), 2.77-2.86 (m, 1H), 2.63 (dd,J=13.1, 2.5 Hz, 1H), 2.15-2.36 (m, 3H), 1.84-1.97 (m, 2H), 1.49 (d,J=11.4 Hz, 1H), 1.02-1.14 (m, 1H), 0.63-0.73 (m, 1H), 0.55-0.63 (m, 1H),0.45-0.53 (m, 1H), 0.37-0.45 (m, 1H); LC/MS, m/z=357 [M+H]⁺ (Calc: 356).

Example 4 (2R,3 aS,4R,9bS)-methyl12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxylate(12)

Conc. HCl (4 mL, 48 mmol) was added to Compound 11 (1.33 g, 3.88 mmol)in 4 mL water and the resulting suspension heated at 80° C. for 18 h.MeOH was added to break up the resulting sludge and the material wasconcentrated to yield 1.28 g of a brown solid that was carried onwithout further purification. To a solution of this solid (1.17 g, 3.4mmol) in 18 mL MeOH was added SOCl₂ (0.81 g, 6.8 mmol) at 0° C. Thesolution was heated at reflux for 2 h and concentrated. DCM was addedand the solution washed with 10% aq. NH₄OH. The resulting sludge wasdecanted off, the organic layer dried over Na₂SO₄, and concentrated toyield crude Compound 12 as a brown oil. Compound 12 was purified bypreparatory HPLC [0-60% ACN/H2O (0.01% TFA)] and isolated as its TFAsalt.

TFA salt of Compound 12: ¹H NMR (DMSO-d₆) δ: 9.28 (br. s., 1H), 8.74(br. s., 1H), 6.93 (d, J=8.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.60 (dd,J=8.3, 2.3 Hz, 1H), 5.96 (br. s., 1H), 4.07 (d, J=4.8 Hz, 1H), 3.40 (s,3H), 3.23-3.37 (m, 2H), 3.09-3.23 (m, 2H), 2.92-3.03 (m, 1H), 2.76-2.87(m, 1H), 2.66 (d, J=13.2 Hz, 1H), 2.19-2.36 (m, 3H), 1.98-2.10 (m, 1H),1.87-1.98 (m, 1H), 1.39-1.53 (m, 1H), 0.98-1.12 (m, 1H), 0.52-0.73 (m,2H), 0.34-0.52 (m, 2H); LC/MS, m/z=358 [M+H]⁺ (Calc: 357).

Example 5(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxylicacid (14)(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxylicacid (15)

Conc. HCl (3.7 mL, 44 mmol) was added to a diastereomeric mixture ofCompound 10 and Compound 11 (1.57 g, 4.4 mmol) in 8 mL of 1:1 MeOH:waterand the resulting suspension heated at 80° C. for 21.5 h. The reactionmixture was concentrated and purified by MPLC (0-15% (10%NH₄OH/MeOH)/DCM) to yield 1.11 g of Compound 13 as a 2:1 α:βdiastereomeric mixture and 218 mg of a 2:1 α:β diastereomeric mixture ofCompound 14 and Compound 15 which were separated by prep-HPLC to yieldeach as its TFA salt.

Compound 13: LC/MS, m/z=472 [M+H]⁺ (Calc: 471).

Compound 14 TFA salt: ¹H NMR (DMSO-d₆) δ: 11.95 (br. s., 1H), 8.75 (br.s., 1H), 7.07 (d, J=8.4 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.78 (dd,J=8.5, 2.3 Hz, 1H), 5.91 (s, 1H), 4.08 (d, J=4.6 Hz, 1H), 3.91 (s, 1H),3.71 (s, 3H), 3.27-3.36 (m, 2H), 3.15-3.27 (m, 2H), 3.09 (q, J=9.2 Hz,1H), 2.98 (d, J=8.4 Hz, 1H), 2.74-2.92 (m, 2H), 2.19-2.35 (m, 3H),1.87-2.09 (m, 2H), 1.52 (d, J=9.5 Hz, 1H), 1.03-1.12 (m, 1H), 0.65-0.73(m, 1H), 0.55-0.64 (m, 1H), 0.45-0.52 (m, 1H), 0.37-0.45 (m, 1H). LC/MS,m/z=458 [M+H]⁺ (Calc: 457).

Compound 15 TFA salt: ¹H NMR (DMSO-d₆) δ: 12.07 (br. s., 1H), 8.69 (br.s., 1H), 7.03 (d, J=8.6 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.77 (dd,J=8.6, 2.4 Hz, 1H), 5.74 (s, 1H), 4.01 (d, J=4.6 Hz, 2H), 3.68 (s, 3H),3.11-3.31 (m, 4H), 2.90 (d, J=10.3 Hz, 1H), 2.72-2.82 (m, 1H), 2.57 (dd,J=12.0, 8.3 Hz, 1H), 2.04-2.32 (m, 4H), 1.75-1.85 (m, 1H), 1.44 (d,J=11.4 Hz, 1H), 0.91-1.04 (m, 1H), 0.57-0.66 (m, 1H), 0.48-0.56 (m, 1H),0.29-0.44 (m, 2H). LC/MS, m/z=358 [M+H]⁺ (Calc: 357).

Example 6(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxylicacid (16)

A 10% aq. solution of NaOH (0.9 mL, 2.3 mmol) was added to Compound 12(270 mg, 0.76 mmol) in 4 mL MeOH and the resulting solution was stirredat RT for 90 min and at 80° C. for 6 h. The reaction was quenched withexcess TFA, concentrated, and purified by preparatory HPLC [0-40%ACN/H₂O (0.01% TFA)] to yield the title Compound 16 as its TFA salt.

Compound 16 TFA salt: ¹H NMR (DMSO-d₆) δ: 11.90 (br. s., 1H), 9.19 (s,1H), 8.65 (br. s., 1H), 6.88 (d, J=8.4 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H),6.52 (dd, J=8.4, 2.2 Hz, 1H), 5.81 (s, 1H), 3.99 (d, J=4.6 Hz, 1H),3.17-3.28 (m, 3H), 2.99-3.13 (m, 2H), 2.90 (d, J=8.8 Hz, 1H), 2.70-2.79(m, 1H), 2.59 (d, J=10.8 Hz, 1H), 2.12-2.28 (m, 3H), 1.88-1.97 (m, 1H),1.79-1.88 (m, 1H), 1.38 (d, J=9.7 Hz, 1H), 0.94-1.05 (m, 1H), 0.56-0.65(m, 1H), 0.47-0.56 (m, 1H), 0.40 (dt, J=9.4, 4.6 Hz, 1H), 0.29-0.37 (m,1H); LC/MS, m/z=344 [M+H]⁺ (Calc: 343).

Example 7((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-yl)(pyrrolidin-1-yl)methanone(19)((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-yl)(pyrrolidin-1-yl)methanone(20)

(a) Rh₂(OAc)₄ (88 mg, 0.2 mmol) was added to a solution of Compound 2(4.09, 10 mmol) and pyrrolidine (0.85 g, 12.0 mmol) in 50 mL toluene.The solution was heated at reflux for 16 h, concentrated, and purifiedby MPLC (0-30% acetone/hexanes) to yield 1.56 g of Compound 17 and 0.86g of Compound 18, both as brown foams.

Compound 17: LC/MS, m/z=453 [M+H]⁺ (Calc: 452).

Compound 18: LC/MS, m/z=453 [M+H]⁺ (Calc: 452).

(b) AcOH (4 drops) was added to Compound 17 (100 mg) in 1 mL MeOH andthe solution heated at 60° C. for 26 h. The solution was concentratedand purified by preparatory HPLC [0-60% ACN/H₂O (0.01% TFA)] to yieldthe title Compound 19 as its TFA salt.

Compound 19 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.75 (br. s., 1H), 7.06 (d,J=8.6 Hz, 1H), 6.83 (d, J=2.6 Hz, 1H), 6.77 (dd, J=8.5, 2.5 Hz, 1H),5.85 (s, 1H), 4.08 (d, J=4.0 Hz, 1H), 3.70 (s, 3H), 3.19-3.41 (m, 5H),3.07-3.19 (m, 3H), 2.98 (d, J=12.1 Hz, 1H), 2.77-2.87 (m, 1H), 2.59 (dd,J=12.7, 3.2 Hz, 1H), 2.16-2.38 (m, 3H), 1.91-1.98 (m, 2H), 1.81-1.91 (m,2H), 1.67-1.80 (m, 2H), 1.49 (d, J=12.1 Hz, 1H), 1.04-1.12 (m, 1H),0.64-0.74 (m, 1H), 0.54-0.64 (m, 1H), 0.46-0.53 (m, 1H), 0.37-0.46 (m,1H); LC/MS, m/z=411 [M+H]⁺ (Calc: 410).

(c) Compound 20 was prepared as its TFA salt in an analogous fashionfrom Compound 18.

Compound 20 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.71 (br. s., 1H), 7.04 (d,J=8.6 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.87 (br. s., 1H), 6.77 (dd,J=8.5, 2.5 Hz, 1H), 4.07 (d, J=5.1 Hz, 1H), 3.69 (s, 3H), 3.31-3.46 (m,3H), 3.21-3.31 (m, 4H), 3.08-3.16 (m, 1H), 2.84-2.97 (m, 2H), 2.73-2.84(m, 2H), 2.14-2.35 (m, 2H), 1.62-1.85 (m, 7H), 1.46 (d, J=12.3 Hz, 1H),0.94-1.07 (m, 1H), 0.58-0.67 (m, 1H), 0.53 (s, 1H), 0.29-0.44 (m, 2H);LC/MS, m/z=411 [M+H]⁺ (Calc: 410).

Example 8(2R,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a-ol(21)(2R,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a,8-diol(22)

(a) A solution of Compound 11 (0.61 g, 1.7 mmol) in 4 mL ACN was addedto (bis(trifluoroacetoxy)iodo)benzene (736 mg, 1.7 mmol) in 4 mL waterand the resulting mixture stirred at RT for 64.5 h. Another aliquot of(bis(trifluoroacetoxy)iodo)benzene (736 mg, 1.7 mmol) was added and themixture stirred for an additional 26.5 h. A 10% aq. solution of HCl wasadded and washed with Et₂O. The aqueous layer was basified with 10% aq.NH₄OH to pH 10-11, and extracted with DCM followed by EtOAc. The DCM andEtOAc layers were combined, dried over Na₂SO₄, and concentrated. Theresulting brown oil was purified by preparatory HPLC [0-40% ACN/H₂O(0.01% TFA)] to yield Compound 21 as its bis-TFA salt.

Compound 21 bis TFA salt: ¹H NMR (DMSO-d₆) δ: 8.93 (br. s., 1H),7.72-7.86 (m, 3H), 7.19 (d, J=8.4 Hz, 1H), 6.88-7.00 (m, 2H), 6.26 (br.s., 1H), 4.17 (d, J=4.4 Hz, 1H), 3.94 (d, J=5.7 Hz, 2H), 3.82 (s, 3H),3.44 (d, J=19.6 Hz, 1H), 3.30-3.41 (m, 1H), 3.22 (dd, J=20.5, 5.7 Hz,1H), 3.08 (d, J=11.7 Hz, 1H), 2.86-2.95 (m, 1H), 2.46-2.53 (m, 2H),2.32-2.43 (m, 2H), 2.21-2.32 (m, 1H), 1.72 (dd, J=13.1, 8.5 Hz, 1H),1.60 (d, J=12.1 Hz, 1H), 1.07-1.18 (m, 1H), 0.69-0.79 (m, 1H), 0.60-0.69(m, 1H), 0.42-0.59 (m, 2H); LC/MS, m/z=329 [M+H]⁺ (Calc: 328).

(b) A 1M solution of BBr₃ (1.3 mL, 1.3 mmol) was added to Compound 21(105 mg, 0.32 mmol) in 2 mL DCM and the resulting suspension stirred atRT for 75 min. The reaction was slowly quenched with MeOH, concentrated,and purified by preparatory HPLC [0-40% ACN/H₂O (0.01% TFA)] to yieldCompound 22 as its bis-TFA salt.

Compound 22 bis TFA salt: ¹H NMR (DMSO-d₆) δ: 9.42 (s, 1H), 8.81 (br.s., 1H), 7.61-7.77 (m, 3H), 7.01 (d, J=8.1 Hz, 1H), 6.61-6.75 (m, 2H),6.10 (s, 1H), 4.06 (d, J=3.7 Hz, 1H), 3.80-3.92 (m, 1H), 3.32 (d, J=19.8Hz, 2H), 3.11 (dd, J=19.4, 5.3 Hz, 1H), 3.00 (d, J=10.8 Hz, 1H),2.77-2.89 (m, 1H), 2.39-2.47 (m, 1H), 2.17-2.37 (m, 4H), 1.66 (dd,J=13.0, 8.6 Hz, 1H), 1.47 (d, J=11.4 Hz, 1H), 1.00-1.11 (m, 1H),0.63-0.72 (m, 1H), 0.53-0.63 (m, 1H), 0.37-0.53 (m, 2H); LC/MS, m/z=315[M+H]⁺ (Calc: 314).

Example 9 Preparation of Compound 23 and Compound 24

DCM (5 mL) and TFA (30 mL) were added to Compound 8 (4 g, crude) and thereaction mixture stirred at RT for 22 h. The solution was concentratedand the residue dissolved in EtOAc, washed with 10% aq. NH₄OH, driedover Na₂SO₄ and concentrated. Purification by MPLC (0-15% MeOH/DCM)yielded 1.57 g of Compound 23 as a brown foam and 1.01 g of Compound 24as a brown oil.

Compound 23 LC/MS, m/z=399 [M+H]⁺ (Calc: 398).

Compound 24 LC/MS, m/z=399 [M+H]⁺ (Calc: 398).

Example 10(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carbonitrile(25)(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carbonitrile(26)

(a) TFAA (0.21 mL, 1.5 mmol) was added dropwise to Compound 23 (199 mg,0.5 mmol) and DIPEA (0.26 mL, 1.5 mmol) in 2 mL THF. The solution wasstirred at RT for 2.75 h and then concentrated. MeOH (2 mL) was addedfollowed by 2.5M aq. NaOH (0.6 mL, 1.5 mmol) and the reaction heated atreflux for 4 h. EtOAc was added, washed with satd. aq. NaHCO₃, driedover Na₂SO₄, and concentrated. The resulting material was purified bypreparatory HPLC [0-60% ACN/H₂O (0.01% TFA)] to yield Compound 25 as itsTFA salt.

Compound 25 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.78 (bs, 1H), 7.06 (d, J=8.8Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.80 (dd, J=8.8, 2.4 Hz, 1H), 6.05 (s,1H), 4.05 (d, J=5.2 Hz, 1H), 3.69 (s, 3H), 3.37-3.15 (m, 4H), 2.94 (d,J=6.8 Hz, 1H), 2.85-2.76 (m, 1H), 2.69 (d, J=13.1 Hz, 1H), 2.36-2.13 (m,4H), 1.77 (dd, J=13.1, 8.1 Hz, 1H), 1.50 (d, J=9.1 Hz, 1H), 1.05-0.92(m, 1H), 0.66-0.57 (m, 1H), 0.56-0.48 (m, 1H), 0.44-0.30 (m, 2H); LC/MS,m/z=339 [M+H]⁺ (Calc: 338).

(b) Compound 26 was prepared analogously from Compound 24.

Compound 26 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.89 (bs, 1H), 7.10 (d, J=8.4Hz, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.84 (dd, J=8.4, 2.2 Hz, 1H), 6.26 (s,1H), 4.11 (d, J=4.9 Hz, 1H), 3.75 (s, 3H), 3.39-3.26 (m, 2H), 3.19 (dd,J=20.4, 6.3 Hz, 1H), 3.05-2.81 (m, 4H), 2.40-2.20 (m, 3H), 2.11-1.99 (m,2H), 1.55 (d, J=11.9 Hz, 1H), 1.12-1.00 (m, 1H), 0.72-0.64 (m, 1H),0.64-0.55 (m, 1H), 0.51-0.36 (m, 2H); LC/MS, m/z=339 [M+H]⁺ (Calc: 338).

Example 11(2S,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a-ol(28)(2S,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a,8-diol(29)

(a) (Bis(trifluoroacetoxy)iodo)benzene (1.51 g, 3.5 mmol) was added toCompound 24 (0.7 g, 1.76 mmol) in 10 mL 1:1 ACN:H₂O and the solutionstirred at RT for 46 h. Another aliquot of(bis(trifluoroacetoxy)iodo)benzene (1.51 g, 3.5 mmol) was added and thereaction stirred for an additional 8 days 20 h. A 10% aq. solution ofHCl was added and washed with Et₂O. The aqueous layer was basified with10% aq. NH₄OH to pH 10-11, and extracted with EtOAc. The EtOAc layer wasdried over Na₂SO₄, and concentrated to yield 480 mg of Compound 27 as ayellow oil. LC/MS, m/z=371 [M+H]⁺ (Calc: 370).

(b) AcOH (8 drops) was added to Compound 27 (190 mg, 0.5 mmol) in 2 mLMeOH and the solution heated at reflux for 24 h and stirred at RT untilthe total time stirring was 3.5 days. The reaction mixture was dilutedwith EtOAc, washed with 10% aq. NH₄OH, dried over Na₂SO₄, andconcentrated to yield 220 mg of crude Compound 28 as a brown oil. Aportion was purified by preparatory HPLC [0-40% ACN/H₂O (0.01% TFA)] toyield the title Compound 28 as its bis-TFA salt.

Compound 28 bis TFA salt: ¹H NMR (DMSO-d₆) δ: 8.87 (bs, 1H), 7.96 (bs,3H), 7.11 (d, J=8.3 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.87 (dd, J=8.3,2.2 Hz, 1H), 6.23 (s, 1H), 4.18 (d, J=4.8 Hz, 2H), 3.75 (s, 3H),3.38-3.19 (m, 3H), 3.02 (d, J=12.3 Hz, 1H), 2.94-2.80 (m, 2H), 2.42-2.19(m, 2H), 2.11-2.02 (m, 2H), 1.85 (dd, J=14.9, 2.2 Hz, 1H), 1.57 (d,J=12.7 Hz, 1H), 1.10-1.00 (m, 1H), 0.73-0.64 (m, 1H), 0.64-0.56 (m, 2H),0.51-0.37 (m, 2H); LC/MS, m/z=329 [M+H]⁺ (Calc: 328).

(c) Compound 29 was synthesized from Compound 28 as described in Example8 and isolated as its bis-TFA salt.

Compound 29 his TFA salt: ¹H NMR (DMSO-d₆) δ: 9.45 (s, 1H), 8.82 (bs,1H), 7.94 (bs, 3H), 6.99 (d, J=8.1 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 6.68(dd, J=8.1, 2.3 Hz, 1H), 6.16 (s, 1H), 4.15 (d, J=5.0 Hz, 1H), 3.33-3.13(m, 4H), 3.01 (d, J=11.2 Hz, 1H), 2.93-2.84 (m, 1H), 2.71 (dd, J=12.0,7.0 Hz, 1H), 2.31-2.23 (m, 2H), 2.13-2.01 (m, 2H), 1.83 (dd, J=15.1, 2.7Hz, 1H), 1.51 (d, J=11.2 Hz, 1H), 1.10-0.99 (m, 1H), 0.72-0.64 (m, 1H),0.64-0.55 (m, 1H), 0.51-0.36 (m, 2H); LC/MS, m/z=315 [M+H]⁺ (Calc: 314).

Example 12(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(30)

A 2.5M aq. NaOH solution (5.4 mL, 13.5 mmol) was added to Compound 24(1.79 g, 4.5 mmol) in 25 mL MeOH. The solution was heated at 80° C. for1.75 h then concentrated. EtOAc was added, washed with satd. aq. NaHCO₃,dried over Na₂SO₄, and concentrated. DCM (10 mL) was added followed bythe slow addition of a 1M solution of BBr₃ in DCM (18 mL, 18 mmol) at 0°C. The solution was stirred at 0° C. for 1 h, quenched with 7M NH₃/MeOHfollowed by MeOH and concentrated. DCM was added and washed with 10% aq.NH₄OH. The resulting sludge was decanted off and the organic layer wasdried over Na₂SO₄ and concentrated. Purification by MPLC (0-15% (10%NH₄OH/MeOH)/DCM) yielded 330 mg of the title Compound 30 as a brownsolid.

¹H NMR (DMSO-d₆) δ: 9.06 (s, 1H), 7.06 (bs, 1H), 6.87 (d, J=8.4, 1H),6.72-6.66 (m, 2H), 6.52 (dd, J=8.4, 2.3, 1H), 4.56 (s, 1H), 3.22 (d,J=5.4, 1H), 2.96 (d, J=18.4, 1H), 2.68 (dd, J=18.0, 5.8, 1H), 2.57-2.52(m, 1H), 2.42-2.21 (m, 4H), 2.11-1.96 (m, 2H), 1.81 (td, J=11.9, 3.1,1H), 1.72 (d, J=6.9, 2H), 1.23 (d, J=11.9, 1H), 0.88-0.76 (m, 2H),0.52-0.41 (m, 2H), 0.15-0.03 (m, 2H); LC/MS, m/z=343 [M+H]⁺ (Calc: 342).

Example 13(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(31)

To Compound 9 (1.66 g, 3.6 mmol, mixture of diastereomers) was added a1M solution of BBr₃ in DCM (13.5 mL, 13.5 mmol) at 0° C. The solutionwas stirred at RT and after 2 h and 6 h additional aliquots of a 1Msolution of BBr₃ in DCM (13.5 mL, 13.5 mmol) were added. After 22.5 hthe reaction was slowly quenched with MeOH and concentrated. DCM (10 mL)followed by TFA (10 mL) was added and the solution stirred at RT for 90min. Concentration followed by MPLC purification (0-15% MeOH/DCM)followed by preparatory HPLC [0-40% ACN/H₂O (0.01% TFA)] yielded thetitle Compound 31 as its TFA salt.

Compound 31 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.20 (s, 1H), 8.67 (br. s,1H), 7.05 (br. s., 1H), 6.93 (d, J=8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H),6.55-6.62 (m, 2H), 5.69-5.82 (m, 1H), 4.04 (d, J=4.0 Hz, 1H), 3.21-3.33(m, 3H), 2.90-3.18 (m, 4H), 2.75-2.90 (m, 1H), 2.15-2.36 (m, 3H), 1.90(d, J=8.8 Hz, 2H), 1.42 (d, J=10.6 Hz, 1H), 1.08 (br. s., 1H), 0.62-0.72(m, 1H), 0.52-0.62 (m, 1H), 0.44-0.52 (m, 1H), 0.36-0.44 (m, 1H); LC/MS,m/z=343 [M+H]⁺ (Calc: 342).

Example 14(2R,3aS,4R,9bS)-N-benzyl-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(33)(2S,3aS,4R,9bS)-N-benzyl-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(34)

Rh₂(OAc)₄ (8 mg, 0.02 mmol) was added to a solution of Compound 2 (409mg, 1 mmol) and benzylamine (129 mg, 1.2 mmol) in 5 mL toluene. Thesolution was heated at reflux for 16 h and concentrated. MeOH (5 mL) andAcOH (4 drops) were added and the solution heated at 60° C. for 20 h.Concentration followed by MPLC purification (0-15% MeOH/DCM) yielded 297mg of Compound 32 as a brown oil (mixture of amide diasteromers). DCM (4mL) was added followed by a 1M solution of BBr₃ in DCM (2.7 mL, 2.7mmol) and the mixture stirred at RT for 90 min. The reaction wasquenched with 7M NH₃/MeOH and concentrated. The resulting material waspurified by MPLC (0-20% (10% NH₄OH/MeOH)/DCM) followed by preparatoryHPLC [0-40% ACN/H₂O (0.01% TFA)] to yield Compound 33 and Compound 34 astheir TFA salts.

Compound 33 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.19 (bs, 1H), 8.65 (bs, 1H),8.07 (t, J=5.9 Hz, 1H), 7.21 (t, J=7.6 Hz, 2H), 7.13 (t, J=6.9 Hz, 1H),6.99 (d, J=6.9 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.0 Hz, 1H),6.55 (dd, J=8.4, 2.0 Hz, 1H), 5.77 (s, 1H), 4.08 (d, J=5.2 Hz, 2H), 4.00(d, J=4.4 Hz, 1H), 3.30-3.16 (m, 2H), 2.91 (d, J=10.1 Hz, 1H), 2.80-2.70(m, 1H), 2.51 (dd, J=13.3, 2.9 Hz, 1H), 2.30-2.11 (m, 3H), 1.89 (d,J=7.8 Hz, 2H), 1.38 (d, J=11.3 Hz, 1H), 1.06-0.95 (m, 1H), 0.65-0.56 (m,1H), 0.56-0.48 (m, 1H), 0.46-0.38 (m, 1H), 0.38-0.30 (m, 1H). LC/MS,m/z=433 [M+H]⁺ (Calc: 432).

Compound 34 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (bs, 1H), 8.75-8.63 (m,2H), 7.30-7.24 (m, 2H), 7.22-7.15 (m, 3H), 6.92 (d, J=8.1 Hz, 1H), 6.71(d, J=2.0 Hz, 1H), 6.59 (dd, J=8.1, 2.0 Hz, 1H), 6.53 (s, 1H), 4.24 (d,J=6.6 Hz, 2H), 4.04 (d, J=4.9 Hz, 1H), 3.31-3.18 (m, 2H), 3.09 (dd,J=18.9, 5.8 Hz, 1H), 2.92 (d, J=10.7 Hz, 1H), 2.81-2.72 (m, 1H),2.70-2.52 (m, 2H), 2.35-2.15 (m, 2H), 1.94 (dd, J=12.4, 8.2 Hz, 1H),1.80 (d, J=6.6 Hz, 2H), 1.42 (d, J=11.5 Hz, 1H), 1.06-0.94 (m, 1H),0.66-0.57 (m, 1H), 0.56-0.48 (m, 1H), 0.44-0.29 (m, 1H). LC/MS, m/z=433[M+H]⁺ (Calc: 432).

The following compounds were prepared in an analogous fashion.Purification was done via preparatory HPLC [0-60% ACN/H₂O (0.01% TFA)]or preparatory HPLC [0-40% ACN/H₂O (0.01% TFA)]:

(a)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-isobutyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 35) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.19 (bs, 1H), 8.72 (s, 1H),7.59 (t, J=5.6 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H),6.58 (dd, J=8.4, 2.2 Hz, 1H), 5.82 (s, 1H), 4.05 (d, J=3.9 Hz, 1H),3.35-3.22 (m, 2H), 3.17-2.92 (m, 3H), 2.87-2.66 (m, 3H), 2.47 (dd,J=13.4, 2.8 Hz, 1H), 2.36-2.16 (m, 2H), 1.91 (d, J=8.4 Hz, 2H), 1.56(sept., J=6.7 Hz, 1H), 2.43 (d, J=11.2 Hz, 1H), 1.14-1.02 (m, 1H), 0.74(dd, J=6.7, 4.4 Hz, 6H), 0.71-0.63 (m, 1H), 0.63-0.53 (m, 1H), 0.52-0.45(m, 1H), 0.44-0.31 (m, 1H); LC/MS, m/z=399 [M+H]⁺ (Calc: 398).

(b) (2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-isobutyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 36) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.30 (bs, 1H), 8.68 (bs,1H), 8.18 (t, J=5.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.75-6.66 (m, 2H),6.59 (dd, J=8.2, 2.1 Hz, 1H), 4.04 (d, J=4.8 Hz, 1H), 3.31-3.18 (m, 2H),3.07 (dd, J=19.3, 5.5 Hz, 1H), 2.96-2.72 (m, 4H), 2.68-2.49 (m, 2H),2.34-2.14 (m, 2H), 1.90-1.79 m, 1H), 1.79-1.67 (m, 2H), 1.62 (sept.,J=6.2 Hz, 1H), 1.42 (d, J=10.3 Hz, 1H), 1.06-0.94 (m, 1H), 0.78 (d, 6.2Hz, 6H), 0.65-0.57 (m, 1H), 0.56-0.47 (m, 1H), 0.44-0.36 (m, 1H),0.36-0.29 (m, 1H); LC/MS, m/z=399 [M+H]⁺ (Calc: 398).

(c)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 37) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.26 (bs, 1H), 8.72 (bs,1H), 8.10 (t, J=6.4 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 6.98-6.97 (m, 3H),6.70 (d, J=2.6 Hz, 1H), 6.62 (dd, J=8.3, 2.6 Hz, 1H), 5.83 (s, 1H), 4.10(d, J=6.4 Hz, 2H), 4.06 (d, J=4.9 Hz, 1H), 3.30-3.24 (m, 2H), 3.18-3.06(m, 2H), 2.99 (d, J=9.1 Hz, 1H), 2.86-2.77 (m, 1H), 2.56 (dd, J=13.3,2.8 Hz, 1H), 2.37-2.18 (m, 6H), 1.95 (d, J=8.4 Hz, 2H), 1.45 (d, J=11.2Hz, 1H), 1.13-1.03 (m, 1H), 0.72-0.64 (m, 1H), 0.63-0.55 (m, 1H),0.53-0.54 (m, 1H), 0.45-0.37 (m, 1H); LC/MS, m/z=447 [M+H]⁺ (Calc: 446).

(d) (2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 38) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.36 (bs, 1H), 8.75 (bs,1H), 8.71 (t, J=5.7 Hz, 1H), 7.16-7.11 (m, 4H), 6.99 (d, J=8.4 Hz, 1H),6.78 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.4, 2.3 Hz, 1H), 6.64 (bs, 1H),4.26 (d, J=5.7 Hz, 2H), 4.11 (d, J=4.4 Hz, 1H), 3.38-3.26 (m, 2H), 3.16(dd, J=19.6, 5.8 Hz, 1H), 2.99 (d, J=9.4 Hz, 1H), 2.88-2.79 (m, 2H),2.76-2.66 (m, 1H), 2.62 (dd, J=12.3, 8.0 Hz, 1H), 2.42-2.24 (m, 5H),1.99 (dd, J=12.3, 8.0 Hz, 1H), 1.90-1.82 (m, 2H), 1.49 (d, J=10.9 Hz,1H), 1.13-1.02 (m, 1H), 0.73-0.65 (m, 1H), 0.63-0.55 (m, 1H), 0.51-0.44(m, 1H), 0.44-0.36 (m, 1H); LC/MS, m/z=447 [M+H]⁺ (Calc: 446).

(e)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 39) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.25 (bs, 2H), 8.72 (bs,1H), 8.02 (t, J=5.7 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 6.88 (d, J=7.7 Hz,2H), 6.71-6.65 (m, 3H), 6.62 (dd, J=8.5, 2.1 Hz, 1H), 5.82 (s, 1H), 4.06(d, J=3.5 Hz, 1H), 4.03 (d, J=5.7 Hz, 2H), 3.36-3.24 (m, 2H), 3.17-3.04(m, 2H), 2.98 (d, J=9.8 Hz, 1H), 2.86-2.77 (m, 1H), 2.54 (dd, J=11.2,2.8 Hz, 1H), 2.36-2.16 (m, 3H), 1.94 (d, J=8.4 Hz, 2H), 1.44 (d, J=11.2Hz, 1H), 1.13-1.02 (m, 1H), 0.73-0.64 (m, 1H), 0.63-0.54 (m, 1H),0.53-0.45 (m, 1H), 0.45-0.37 (m, 1H); LC/MS, m/z=449 [M+H]⁺ (Calc: 448).

(f) (2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 40) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.36 (bs, 1H), 9.34 (bs,1H), 8.76 (bs, 1H), 8.56 (t, J=5.7 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 6.98(d, J=8.3 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.74-6.69 (m, 3H), 6.66 (dd,J=8.3, 2.4 Hz, 1H), 4.19 (dd, J=5.7 Hz, 2H), 4.11 (d, J=5.2 Hz, 1H),3.38-3.26 (m, 2H), 3.15 (dd, J=19.3, 5.9 Hz, 1H), 2.99 (d, J=11.1 Hz,1H), 2.88-2.79 (m, 1H), 2.75-2.66 (m, 1H), 2.61 (dd, J=11.9, 8.1 Hz,1H), 2.42-2.20 (m, 2H), 1.97 (dd, J=11.9, 8.1 Hz, 1H), 1.88-1.80 (m,2H), 1.49 (d, J=10.4 Hz, 1H), 1.13-1.02 (m, 1H), 0.73-0.64 (m, 1H),0.64-0.55 (m, 1H), 0.51-0.44 (m, 1H), 0.44-0.36 (m, 1H); LC/MS, m/z=449[M+H]⁺ (Calc: 448).

(g)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 41) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.32 (s, 1H), 9.24 (bs, 1H),9.07 (bs, 1H), 8.71 (bs, 1H), 8.00 (t, J=5.8 Hz, 1H), 6.95 (s, J=8.2 Hz,1H), 6.68 (d, J=2.2 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.61 (dd, J=8.3,2.2 Hz, 1H), 6.22 (d, J=2.4 Hz, 1H), 6.14 (dd, J=8.3, 2.2 Hz, 1H), 5.81(s, 1H), 4.06 (d, J=3.7 Hz, 1H), 3.96 (t, J=4.8 Hz, 2H), 3.35-3.23 (m,2H), 3.19-3.06 (m, 2H), 2.97 (d, J=10.3 Hz, 1H), 2.86-2.77 (m, 1H),2.57-2.52 (m, 1H), 2.36-2.16 (m, 3H), 1.93 (d, J=8.8 Hz, 2H), 1.44 (d,J=11.0 Hz, 1H), 1.15-1.02 (m, 1H), 0.73-0.64 (m, 1H), 0.63-0.54 (m, 1H),0.53-0.45 (m, 1H), 0.43-0.37 (m, 1H); LC/MS, m/z=465 [M+H]⁺ (Calc: 464).

(h) (2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 42) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.41 (s, 1H), 9.36 (s, 1H),9.16 (s, 1H), 8.76 (bs, 1H), 8.50 (t, J=5.4 Hz, 1H), 6.98 (d, J=8.4 Hz,1H), 6.86 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.77 (d, J=2.1 Hz, 1H), 6.66(dd, J=8.4, 2.1 Hz, 1H), 6.28 (d, J=2.1 Hz, 1H), 6.17 (dd, J=8.4, 2.1Hz, 1H), 4.17-4.06 (m, 3H), 3.37-3.26 (m, 2H), 3.15 (dd, J=18.9, 5.5 Hz,1H), 2.99 (d, J=10.2 Hz, 1H), 2.88-2.79 (m, 1H), 2.79-2.70 (m, 1H), 2.61(dd, J=12.6, 7.9 Hz, 1H), 2.42-2.22 (m, 2H), 1.95 (dd, J=12.6, 7.9 Hz,1H), 1.87-1.77 (m, 2H), 1.49 (d, J=11.8 Hz, 1H), 1.13-1.02 (m, 1H),0.73-0.65 (m, 1H), 0.63-0.55 (m, 1H), 0.51-0.44 (m, 1H), 0.44-0.36 (m,1H); LC/MS, m/z=465 [M+H]⁺ (Calc: 464).

(i)(2R,3aS,4R,9bS)-N-(4-chlorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 43) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (bs, 1H), 8.73 (bs,1H), 8.18 (t, J=5.9 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.06 (d, J=8.5 Hz,2H), 6.96 (d, J=8.5 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 6.63 (dd, J=8.5,2.3 Hz, 1H), 5.85 (s, 1H), 4.14 (t, J=5.1 Hz, 2H), 4.07 (d, J=4.4 Hz,1H), 3.36-3.24 (m, 2H), 3.19-3.07 (m, 2H), 2.99 (d, J=9.5 Hz, 1H),2.87-2.77 (m, 1H), 2.58 (d, J=13.2 Hz, 1H), 2.36-2.18 (m, 3H), 1.96 (d,J=8.8 Hz, 2H), 1.45 (d, J=10.3 Hz, 1H), 1.13-1.03 (m, 1H), 0.72-0.64 (m,1H), 0.63-0.55 (m, 1H), 0.53-0.45 (m, 1H), 0.45-0.37 (m, 1H); LC/MS,m/z=467 [M+H]⁺ (Calc: 466).

(j)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 44) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.30 (bs, 1H), 8.74 (bs,1H), 8.21 (t, J=6.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.0,2.0 Hz, 1H), 6.98-6.92 (m, 2H), 6.71 (d, J=2.0 Hz, 1H), 6.63 (dd, J=8.0,2.0 Hz, 1H), 5.88 (s, 1H), 4.16 (d, J=6.0 Hz, 2H), 4.08 (d, J=3.9 Hz,1H), 3.37-3.24 (m, 2H), 3.22-3.07 (m, 2H), 2.99 (d, J=9.4 Hz, 1H),2.87-2.77 (m, 1H), 2.61 (dd, J=13.4, 2.8 Hz, 1H), 2.37-2.18 (m, 3H),1.97 (d, J=9.5 Hz, 2H), 1.46 (d, J=10.3 Hz, 1H), 1.14-1.02 (m, 1H),0.73-0.63 (m, 1H), 0.63-0.55 (m, 1H), 0.53-0.45 (m, 1H), 0.45-0.37 (m,1H); LC/MS, m/z=501 [M+H]⁺ (Calc: 500).

(k) (2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 45) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.39 (bs, 1H), 8.76 (bs,1H), 8.70 (t, J=5.9 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.44 (dd, J=8.3,1.8 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.79 (d,J=2.2 Hz, 1H), 6.67 (dd, J=8.3, 2.2 Hz, 1H), 6.37 (s, 1H), 4.40-4.29 (m,2H), 4.11 (d, J=4.8 Hz, 1H), 3.37-3.26 (m, 2H), 3.16 (dd, J=19.2, 5.6Hz, 1H), 2.99 (d, J=9.6 Hz, 1H), 2.89-2.79 (m, 1H), 2.78-2.67 (m, 1H),2.62 (dd, J=12.8, 8.8 Hz, 1H), 2.41-2.23 (m, 2H), 2.02 (dd, J=12.8, 8.8Hz, 1H), 1.94-1.85 (m, 2H), 1.49 (d, J=11.2 Hz, 1H), 1.13-1.01 (m, 1H),0.72-0.64 (m, 1H), 0.63-0.54 (m, 1H), 0.51-0.43 (m, 1H), 0.43-0.35 (m,1H); LC/MS, m/z=501 [M+H]⁺ (Calc: 500).

(l) (2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 46) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.27 (s, 1H), 8.73 (bs, 1H),8.23 (t, J=6.1 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H),6.99 (dd, J=8.4, 1.9 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.68 (d, J=2.3 Hz,1H), 6.61 (dd, J=8.4, 2.3 Hz, 1H), 5.86 (s, 1H), 4.14 (d, J=6.1 Hz, 2H),4.07 (d, J=3.9 Hz, 1H), 3.34-3.23 (m, 2H), 3.18-3.07 (m, 2H), 2.98 (d,J=10.0 Hz, 1H), 2.86-2.77 (m, 1H), 2.56 (dd, 13.1, 2.3 Hz, 1H),2.37-2.17 (m, 3H), 2.01-1.88 (m, 2H), 1.45 (d, 11.6, 1H), 1.13-1.02 (m,1H), 0.72-0.64 (m, 1H( ), 0.63-0.55 (m, 1H), 0.53-0.45 (m, 1H),0.45-0.36 (m, 1H); LC/MS, m/z=501 [M+H]⁺ (Calc: 500).

(m) (2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 47) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.36 (s, 1H), 8.80-8.69 (m,2H), 7.61 (d, J=8.4 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.25 (dd, J=8.4,1.8 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 6.67 (dd,J=8.1, 2.2 Hz, 1H), 6.39 (s, 1H), 4.30 (d, J=6.2 Hz, 2H), 4.11 (d, J=4.1Hz, 1H), 3.37-3.24 (m, 2H), 3.16 (dd, J=20.2, 6.2 Hz, 1H), 2.99 (d,J=9.3 Hz, 1H), 2.88-2.78 (m, 1H), 2.74-2.57 (m, 2H), 2.41-2.22 (m, 2H),2.02 (dd, J=11.7, 7.8 Hz, 1H), 1.92-1.85 (m, 2H), 1.49 (d, J=11.7 Hz,1H), 1.12-1.01 (m, 1H), 0.73-0.64 (m, 1H), 0.63-0.54 (m, 1H), 0.51-0.44(m, 1H), 0.44-0.36 (m, 1H); LC/MS, m/z=501 [M+H]⁺ (Calc: 500).

(n)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(4-fluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 48) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (bs, 1H), 8.73 (bs,1H), 8.16 (t, J=5.9 Hz, 1H), 7.14-7.04 (m, 4H), 6.96 (d, J=8.5 Hz, 1H),6.70 (d, J=2.1 Hz, 1H), 6.63 (dd, J=8.5, 2.1 Hz, 1H), 5.85 (s, 1H), 4.13(d, J=5.9 Hz, 1H), 4.07 (d, J=4.3 Hz, 1H), 3.36-3.24 (m, 2H), 3.18-3.07(m, 2H), 2.99 (d, J=10.4 Hz, 1H), 2.87-2.77 (m, 1H), 2.57 (dd, J=13.2,2.9 Hz, 1H), 2.37-2.17 (m, 3H), 1.96 (d, J=8.9 Hz, 2H), 1.45 (d, J=11.6Hz, 1H), 1.13-1.03 (m, 1H), 0.73-0.64 (m, 1H), 0.63-0.55 (m, 1H),0.53-0.45 (m, 1H), 0.45-0.37 (m, 1H); LC/MS, m/z=451 [M+H]⁺ (Calc: 450).

(o)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 49) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.20 (bs, 1H), 8.74 (bs,1H), 8.25 (t, J=5.9 Hz, 1H), 7.06 (tt, J=9.3, 2.3 Hz, 1H), 6.74 (d,J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 6.67 (d, J=2.3 Hz, 1H), 6.59 (dd,J=8.4, 2.3 Hz, 1H), 5.86 (s, 1H), 4.16 (dd, J=9.0, 5.9 Hz, 2H), 4.07 (d,J=4.5 Hz, 1H), 3.35-3.32 (m, 2H), 3.19-3.07 (m, 2H), 2.98 (d, J=10.8 Hz,1H), 2.87-2.78 (m, 1H), 2.56 (dd, J=12.8, 2.8 Hz, 1H), 2.37-2.18 (m,3H), 2.04-1.87 (m, 2H), 1.45 (d, J=11.2 Hz, 1H), 1.13-1.03 (m, 1H),0.72-0.63 (m, 1H), 0.63-0.54 (m, 1H), 0.53-0.45 (m, 1H), 0.45-0.36 (m,1H); LC/MS, m/z=469 [M+H]⁺ (Calc: 468).

(p)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 50) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.23 (s, 1H), 8.71 (bs, 1H),7.70 (t, J=5.3 Hz, 1H), 7.27 (t, J=7.1 Hz, 2H), 7.22-7.16 (m, 1H), 7.10(d, J=7.1 Hz, 2H), 6.95 (d, J=8.3 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.60(dd, J=8.3, 2.4 Hz, 1H), 5.82 (s, 1H), 4.05 (d, J=4.8 Hz, 1H), 3.35-3.24(m, 2H), 3.16-3.06 (m, 3H), 3.06-2.92 (m, 2H), 2.86-2.77 (m, 1H), 2.59(t, J=6.9 Hz, 2H), 2.35-2.13 (m, 3H), 1.89 (d, J=8.3 Hz, 2H), 1.43 (d,J=9.6 Hz, 1H), 1.13-1.03 (m, 1H), 0.72-0.64 (m, 1H), 0.63-0.55 (m, 1H),0.53-0.45 (m, 1H), 0.45-0.37 (m, 1H); LC/MS, m/z=447 [M+H]⁺ (Calc: 446).

(q) (2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 51) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.38 (bs, 1H), 8.75 (bs,1H), 8.36 (t, J=5.7 Hz, 1H), 7.33-7.26 (m, 2H), 2.24-7.17 (m, 3H), 6.98(d, J=8.3 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 6.70 (bs, 1H), 6.66 (dd,J=8.3, 2.2 Hz, 1H), 4.10 (d, J=5.6 Hz, 1H), 3.40-3.23 (m, 4H), 3.14 (dd,J=19.7, 5.6 Hz, 1H), 2.99 (d, J=9.8 Hz, 1H), 2.88-2.79 (m, 1H), 2.73 (t,J=7.0 Hz, 2H), 2.68-2.52 (m, 2H), 2.40-2.22 (m, 4H), 1.88 (dd, J=12.9,8.3 Hz, 1H), 1.83-1.72 (m, 2H), 1.48 (d, J=11.1 Hz, 1H), 1.13-1.01 (m,1H), 0.72-0.64 (m, 1H), 0.63-0.54 (m, 1H), 0.51-0.43 (m, 1H), 0.43-0.35(m, 1H); LC/MS, m/z=447 [M+H]⁺ (Calc: 446).

(r) (2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-3-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 89): LC/MS, m/z=434.2 [M+H]⁺ (Calc: 433.2).

(s)(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-4-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 90): LC/MS, m/z=434.2 [M+H]⁺ (Calc: 433.2).

(t)(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-3-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 92): LC/MS, m/z=434.2 [M+H]⁺ (Calc: 433.2).

Example 15((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(piperidin-1-yl)methanone(56)((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(piperidin-1-yl)methanone(57)

Rh₂(OAc)₄ (8 mg, 0.02 mmol) was added to a solution of Compound 2 (409mg, 1 mmol) and piperidine (102 mg, 1.2 mmol) in 5 mL toluene. Thesolution was heated at reflux for 16 h and concentrated. MeOH (5 mL) andAcOH (4 drops) were added and the solution heated at 60° C. for 20 h.Concentration followed by MPLC purification (0-15% MeOH/DCM) yielded 141mg of Compound 52 as a brown oil and Compound 53. MeOH (2 mL) and AcOH(5 drops) were added to Compound 52 and the solution heated at refluxfor 3.5 days and concentrated to yield 109 mg of Compound 54 as a brownoil. Similarly Compound 53 was converted to Compound 55. DCM (4 mL) wasadded separately to Compound 54 and Compound 55 followed by a 1Msolution of BBr₃ in DCM (4 equiv.) and each mixture stirred at RT for 90min Each reaction was quenched with 7M NH₃/MeOH and concentrated. Theresulting material from Compound 54 was purified by MPLC (0-20% (10%NH₄OH/MeOH)/DCM) to yield the title Compound 56 as its HBr salt. Theresulting material from Compound 55 was purified by MPLC (0-20% (10%NH₄OH/MeOH)/DCM) followed by preparatory HPLC [0-40% ACN/H₂O (0.01%TFA)] to yield the title Compound 57 as its TFA salt.

Compound 56 HBr salt: ¹H NMR (DMSO-d₆/DCl) δ: 6.89 (d, J=8.3 Hz, 1H,partially obscurred by DCl), 6.63 (d, J=2.1 Hz, 1H), 6.56 (dd, J=8.3,2.1 Hz, 1H), 4.09 (d, J=5.2 Hz, 1H), 3.43-3.15 (m, 7H), 3.07 (dd,J=19.1, 5.2 Hz, 1H), 2.94 (dd, J=12.5, 3.5 Hz, 1H), 2.81 (dd, J=13.2,7.3 Hz, 1H), 2.39-2.09 (m, 4H), 1.98-1.85 (m, 2H), 1.57-1.21 (m, 7H),1.08-0.98 (m, 1H), 0.66-0.57 (m, 1H), 0.57-0.42 (m, 2H), 0.39-0.31 (m,1H). LC/MS, m/z=411 [M+H]⁺ (Calc: 410).

Compound 57 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.12 (bs, 1H), 8.49 (bs, 1H),6.74 (d, J=8.1 Hz, 1H), 6.55 (d, J=2.5 Hz, 1H), 6.41 (dd, J=8.1, 2.5 Hz,1H), 6.32 (s, 1H), 3.85 (d, J=5.6 Hz, 1H), 3.32-3.01 (m, 6H), 2.96-2.80(m, 2H), 2.74 (d, J=10.6 Hz, 1H), 2.63-2.54 (m, 1H), 2.34 (dd, J=12.6,8.6 Hz, 1H), 2.13-1.97 (m, 2H), 1.74 (dd, J=12.6, 8.6 Hz, 1H), 1.69-1.59(m, 2H), 1.40-1.28 (m, 2H), 1.27-1.13 (m, 5H), 0.87-0.76 (m, 1H),0.48-0.39 (m, 1H), 0.38-0.30 (m, 1H), 0.26-0.19 (m, 1H), 0.19-0.10 (m,1H). LC/MS, m/z=411 [M+H]⁺ (Calc: 410).

The following compounds were prepared in an analogous manner:

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(morpholino)methanone(Compound 58) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.22 (s, 1H), 8.73 (bs, 1H),6.94 (d, J=8.4 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H), 6.58 (dd, J=8.4, 2.2 Hz,1H), 5.83 (s, 1H), 4.07 (d, J=4.5 Hz, 1H), 3.68-3.32 (m, 12H,overlapping with H₂O), 3.14 (dd, J=19.1, 5.1 Hz, 1H), 2.97 (d, J=10.1Hz, 1H), 2.86-2.76 (m, 1H), 2.44 (dd, J=13.0, 3.4 Hz, 1H), 2.36-2.18 (m,3H), 2.06 (dd, J=13.0, 9.0 Hz, 1H), 1.88 (dd, J=13.0, 7.9 Hz, 1H), 1.45(d, J=11.3 Hz, 1H), 1.12-1.01 (m, 1H), 0.73-0.64 (m, 1H), 0.63-0.54 (m,1H), 0.52-0.45 (m, 1H), 0.45-0.36 (m, 1H). LC/MS, m/z=413 [M+H]⁺ (Calc:412).

((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(thiomorpholino)-methanone(Compound 87): LC/MS, m/z=429.1 [M+H]⁺ (Calc: 428.1).

((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(1,1-dioxido-thiomorpholino)methanone(Compound 94): LC/MS, m/z=461.2 [M+H]⁺ (Calc: 460.2).

(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N,N-diethyl-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(Compound 59) TFA salt: ¹H NMR (DMSO-d₆) δ: 9.18 (s, 1H), 8.74 (bs, 1H),6.94 (d, J=7.9 Hz, 1H), 6.63 (d, J=2.1 Hz, 1H), 6.58 (dd, J=7.9, 2.1 Hz,1H), 5.88 (s, 1H), 4.07 (d, J=4.8 Hz, 1H), 3.43-3.19 (m, 7H, overlappingwith H₂O), 3.13 (dd, J=18.7, 5.4 Hz, 1H), 3.09-2.93 (m, 2H), 2.86-2.77(m, 1H), 2.40-2.17 (m, 4H), 2.06 (dd, J=13.9, 10.9 Hz, 1H), 1.92-1.83(m, 1H), 1.43 (d, J=11.5 Hz, 1H), 1.13 (t, J=7.2 Hz, 3H), 1.10-1.03 (m,1H), 0.91 (t, J=7.2 Hz, 3H), 0.72-0.63 (m, 1H), 0.63-0.54 (m, 1H),0.54-0.46 (m, 1H), 0.45-0.37 (m, 1H). LC/MS, m/z=399 [M+H]⁺ (Calc: 398).

Example 16(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N,N-dimethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(62)(2R,3aS,4R,9bS)-N-(2-amino-2-oxoethyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(64)2-((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamido)aceticacid (66)

(a) Two drops of DMF were added to Compound 14 (1.42 g, 3.97 mmol) andoxalyl chloride (1.01 g, 7.95 mmol) in 20 mL DCM and the solution wasstirred at RT for 2 h. The solution was concentrated to yield 1.46 g ofCompound 60 as a brown solid that was carried on without furtherpurification.

(b) Compound 60 (0.2 g, 0.53 mmol) was added to a 2M solution ofdimethylamine in THF (1.33 mL, 2.66 mmol) and the mixture stirred at RTfor 75 min DCM was added, washed with satd aq. NaHCO₃, passed through aphase separation column, and concentrated to yield 156 mg of Compound61. Compound 61 was O-demethylated as described in Example 14 andpurified by MPLC (0-20% (10% NH₄OH/MeOH)/DCM) to yield the titleCompound 62 as its HBr salt: ¹H NMR (DMSO-d₆) δ: 9.23 (s, 1H), 8.76 (bs,1H), 6.93 (d, J=8.3 Hz, 1H), 6.65 (s, 1H), 6.59 (d, J=8.3 Hz, 1H), 5.90(s, 1H), 4.08 (s, 1H), 3.46-3.22 (m, 4H, overlapping with H₂O), 3.13(dd, J=18.8, 4.2 Hz, 1H), 2.99 (s, 1H), 2.93-2.88 (m, 1H), 2.87-2.76 (m,1H), 2.71 (s, 3H), 2.47-2.16 (m, 4H), 2.05-1.86 (m, 2H), 1.44 (d, J=12.5Hz, 1H), 1.13-1.02 (m, 1H), 0.73-0.63 (m, 1H), 0.63-0.54 (m, 1H),0.54-0.46 (m, 1H). 0.46-0.36 (m, 1H); LC/MS, m/z=371 [M+H]⁺ (Calc: 370).

(c) Compound 60 (0.2 g, 0.53 mmol) was added to glycinamide-HCl (71 mg,0.63 mmol) and DIPEA (0.28 mL, 1.60 mmol) in 2 mL DCM and the solutionstirred at RT for 75 min. DCM was added, washed with satd. aq. NaHCO₃,passed through a phase separation column, and concentrated to yield 144mg of Compound 63. Compound 63 was O-demethylated as described inExample 14 and purified by MPLC (0-20% (10% NH₄OH/MeOH)/DCM) to yieldthe title Compound 64 as its HBr salt.

Compound 64 HBr salt: ¹H NMR (DMSO-d₆/DCl) δ: 6.89 (d, J=8.2 Hz, 1H),6.62 (d, J=2.1 Hz, 1H), 6.55 (dd, J=8.2, 2.1 Hz, 1H), 4.10 (d, J=5.4 Hz,1H), 3.45 (s, 2H), 3.26-2.99 (m, 5H), 2.94 (d, J=11.7 Hz, 1H), 2.82 (dd,J=13.4, 7.3 Hz, 1H), 2.44 (d, J=11.7 Hz, 1H), 2.27 (td, J=12.9, 4.5 Hz,1H), 1.98 (dd, J=12.9, 8.4 Hz, 1H), 1.77 (dd, J=12.9, 9.5 Hz, 1H), 1.34(d, J=11.9 Hz, 1H), 1.24 (dd, J=14.3, 6.4 Hz, 1H), 1.08-0.97 (m, 1H),0.65-0.57 (m, 1H), 0.57-0.50 (m, 1H). 0.50-0.42 (m, 1H), 0.39-0.30 (m,1H); LC/MS, m/z=400 [M+H]⁺ (Calc: 399).

(d) Compound 60 (0.2 g, 0.53 mmol) was added to sarcosine ethylester-HCl (98 mg, 0.63 mmol) and DIPEA (0.28 mL, 1.60 mmol) in 2 mL DCMand the solution stirred at RT for 75 min. DCM was added, washed withsatd. aq. NaHCO₃, passed through a phase separation column, andconcentrated to yield 206 mg of Compound 65. DCM (2 mL) was addedfollowed by a 1M solution of BBr₃ in DCM (1.8 mL, 1.8 mmol) and themixture stirred at RT for 90 min. The reaction was quenched with MeOHand concentrated. EtOH (2 mL) was added followed by 2.5M NaOH (0.9 mmol,2.25 mmol) and the reaction mixture stirred at RT for 5 days followed by1 h at reflux. The solution was concentrated and purified by MPLC (0-20%(10% NH₄OH/MeOH)/DCM) followed by preparatory HPLC [0-40% ACN/H₂O (0.01%TFA)] to yield the title Compound 66 as its TFA salt.

Compound 66 TFA salt: ¹H NMR (DMSO-d₆) δ: 12.96 (bs, 0.35H), 12.52 (bs,0.65H), 9.25 (s, 0.35H), 9.19 (s, 0.65H), 8.72 (bs, 1H), 6.97-6.90 (m,1H), 6.66-6.61 (m, 1H), 6.61-6.56 (m, 1H), 5.87 (s, 0.65H), 5.82 (s,0.35H), 4.14 (d, J=7.3 Hz, 0.65H), 4.10-4.03 (m, 1H), 3.87 (dd, J=17.2,23.1 Hz, 1.35H), 3.34-3.22 (m, 4H), 3.18-3.06 (m, 1H), 3.04 (s, 2H),2.98 (d, J=11.2 Hz, 1H), 2.86-2.76 (m, 1H), 2.71 (s, 1H), 2.49-2.42 (m,1H), 2.39-2.17 (m, 3H), 2.02-1.82 (m, 2H), 1.49-1.39 (m, 1H), 1.13-1.02(m, 1H), 0.72-0.63 (m, 1H), 0.63-0.54 (m, 1H), 0.53-0.45 (m, 1H),0.45-0.37 (m, 1H); LC/MS, m/z=415 [M+H]⁺ (Calc: 414).

Example 17 Preparation of Compounds 71-74

(a) Ac₂O (12.5 mL, 132 mmol) was added to Compound 67 (5.0 g, 13.25mmol) and the solution heated at 120° C. for 24 h. The reaction mixturewas diluted with EtOAc, washed with two portions of satd. aq. NaHCO₃,dried over Na₂SO₄, and concentrated. ACN (75 mL) and4-acetamidobenzenesulfonyl azide (6.36 g, 26.5 mmol) were added,followed by DBU (6.0 mL, 39.7 mmol) at 0° C. The reaction was allowed towarm to RT over 18 h and 4-acetamidobenzenesulfonyl azide (3.1 g, 13.25mmol) was added, followed by DBU (3 mL, 19.9 mmol). The reaction wasstirred for an additional 3 days and concentrated. EtOAc was added,washed with two portions of 1M aq. NaOH, dried over Na₂SO₄ andconcentrated. The resulting material was carried on without furtherpurification to yield 7.47 g of Compound 68 as a brown foam. LC/MS,m/z=446 [M+H]⁺ (Calc: 445).

(b) Rh₂(OAc)₄ (117 mg, 0.27 mmol) was added to a solution of Compound 68(5.90 g, 13.25 mmol) and 2,4-dimethoxybenzylamine (2.44 g, 14.6 mmol) in75 mL toluene. The solution was heated at reflux for 15 h andconcentrated to yield Compound 69 as a mixture of diastereomers. DCM (15mL) followed by TFA (60 mL) were added and the solution stirred at RTfor 27 h then concentrated. EtOAc was added, washed with two portions of10% aq. NH₄OH, dried over Na₂SO₄, and concentrated. The crude materialwas purified by MPLC (0-10% MeOH/DCM) to yield 6.14 g of Compound 70 asa diastereomeric mixture that was carried on without furtherpurification. LC/MS, m/z=435 [M+H]⁺ (Calc: 434).

(c) MeOH (32 mL) was added to Compound 70 (6.14 g, 13.25 mmol) followedby a 2.5M aq. NaOH solution (15.9 mL, 39.8 mmol). The reaction mixturewas heated at 80° C. for 1 h and concentrated. EtOAc was added, washedwith satd. aq. NaHCO₃, dried over Na₂SO₄, and concentrated. Purificationby MPLC (0-20% (10% NH₄OH/MeOH)/DCM) yielded 1.21 g of Compound 71 as abrown oil and 2.89 g of Compound 72 as a brown oil.

Compound 71: ¹H NMR (DMSO-d₆) δ: 7.40-7.35 (m, 2H), 7.35-7.29 (m, 2H),7.28-7.22 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.96 (s, 1H), 6.76 (d, J=2.6Hz, 1H), 6.66 (dd, J=8.4, 2.6 Hz, 1H), 6.49 (s, 1H), 4.35 (s, 1H),3.75-3.59 (m, 5H), 3.22-3.14 (m, 1H), 3.01 (d, J=4.9 Hz, 1H), 3.00-2.90(m, 1H), 2.69 (dd, J=18.1, 5.3 Hz, 1H), 2.53 (dd, J=12.3, 3.1 Hz, 1H),2.38-2.30 (m, 1H), 2.12-1.97 (m, 2H), 1.86 (td, J=11.5, 3.1 Hz, 1H),1.72-1.58 (m, 2H), 1.27 (d, J=12.3 Hz, 1H). LC/MS, m/z=393 [M+H]⁺ (Calc:392).

Compound 72: ¹H NMR (DMSO-d₆) δ: 7.40-7.35 (m, 2H), 7.35-7.30 (m, 2H),7.28-7.21 (m, 1H), 7.08 (s, 1), 7.05 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.8Hz, 1H), 6.76-6.69 (m, 2H), 4.60 (s, 1H), 3.73 (s, 3H), 3.71-3.63 (m,2H), 3.21-3.13 (m, 1H), 3.02 (d, J=5.5 Hz, 1H), 2.73 (dd, J=18.0, 5.5Hz, 1H), 2.47 (dd, J=12.0, 7.8 Hz, 1H), 2.39-2.31 (m, 1H), 2.31-2.23 (m,1H), 2.08-1.98 (m, 2H), 1.93-1.84 (m, 1H), 1.69 (d, J=7.8 Hz, 2H), 1.27(d, J=12.0 Hz, 1H). LC/MS, m/z=393 [M+H]⁺ (Calc: 392).

(d) AcOH (70 mL) was added to Compound 71 (2.89 g, 7.4 mmol). Pd(OH₂) oncarbon (0.3 g, ˜10% w/w) was added and the reaction mixture shaken onthe Parr shaker at 50 psi of H₂ for 69 h. The mixture was filteredthrough Celite, the solids washed with MeOH, and the filtrateconcentrated. EtOAc was added to the resulting oil, washed with threeportions of 10% aq. NH₄OH, dried over Na₂SO₄ and concentrated to yield abrown oil. The combined aqueous layers were concentrated, combined withthe material from the organic layer, and purified by MPLC (0-20% (10%NH₄OH/MeOH)/DCM) to yield Compound 73 as a brown oil. LC/MS, m/z=393[M+H]⁺ (Calc: 392).

Compound 74 was prepared analogously from Compound 72. LC/MS, m/z=393[M+H]⁺ (Calc: 392).

Example 18(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(75)(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(76)

(a) 2,2,2-Trifluoroethyl trifluoromethanesulfonate (154 mg, 0.66 mmol)was added to Compound 74 (0.2 g, 0.66 mmol) and DIPEA (0.35 mL, 1.98mmol) in 3 mL ACN and the solution was heated at reflux. After 16 h2,2,2-trifluoroethyl trifluoromethanesulfonate (383 mg, 1.65 mmol) wasadded and the solution heated at reflux for an additional 5 h. Thereaction mixture was concentrated and the resulting material suspendedin DCM (2 mL). A 1M solution of BBr₃ in DCM (2.65 mL, 2.65 mmol) wasadded and the mixture stirred at RT for 2 h. The solution was quenchedby the addition of 1.5 mL 7M NH₃/MeOH and concentrated. Salts wereremoved by filtration and the resulting material was purified by MPLC(0-20% (10% NH₄OH/MeOH)/DCM) to yield the title Compound 76.

Compound 76: ¹H NMR (DMSO-d₆) δ: 9.20 (bs, 1H), 7.43 (bs, 1H), 7.01 (bs,1H), 6.91 (d, J=8.5 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 6.59 (dd, J=8.5,2.2 Hz, 1H), 3.76 (bs, 1H), 3.58 (bs, 1H), 3.34 (bs, 1H), 3.13-2.94 (m,2H), 2.67 (bs 1H), 2.48-2.40 (m, 2H), 2.36-2.19 (m, 2H), 2.00-1.89 (m,1H), 1.77-1.68 (m, 2H), 1.26 (d, J=11.0 Hz, 1H); LC/MS, m/z=371 [M+H]⁺(Calc: 370).

(b) Compound 75 was prepared in an analogous manner:

Compound 75: ¹H NMR (DMSO-d₆) δ: 8.98 (bs, 1H), 6.92 (bs, 1H), 6.78 (d,J=8.3 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 6.45 (bs, 1H), 6.43 (dd, J=8.3,2.4 Hz, 1H), 3.48 (bs, 1H), 3.27 (bs, 1H), 3.12 (bs, 1H), 3.01-2.84 (m,2H), 2.78 (d, J=18.4 Hz, 1H), 2.54-2.45 (m, 1H), 2.39 (dd, J=12.8, 3.3Hz, 1H). 2.17-1.95 (m, 3H), 1.64 (d, J=9.2 Hz, 2H), 1.18 (d, J=11.4 Hz,1H); LC/MS, m/z=371 [M+H]⁺ (Calc: 370).

Example 19(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(77)(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide(78)

(a) Formaldehyde (37% in H₂O, 0.15 mL, 1.98 mmol) was added to Compound74 (0.2 g, 0.66 mmol) in 3 mL DCM and the solution stirred at RT for 10min. NaBH(OAc)₃ (280 mg, 1.32 mmol) was added and the solution stirredat RT for 4 h. DCM was added, washed with satd. aq. NaHCO₃, passedthrough a phase separation column, and concentrated. O-Demethylation wasdone as described in Example 17. Purification by MPLC (0-20% (10%NH₄OH/MeOH)/DCM) followed by preparatory HPLC [0-40% ACN/H₂O (0.01%TFA)] yielded the title Compound 78 as its TFA salt.

Compound 78 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.36 (s, 1H), 9.03 (bs, 1H,7.71 (s, 1H), 7.25 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.76 (d, J=2.4 Hz,1H), 6.66 (dd, J=8.4, 2.4 Hz, 1H), 6.58 (s, 1H), 3.78 (d, J=4.6 Hz, 1H),3.30 (d, J=19.4 Hz, 1H), 3.11 (dd, J=19.4, 5.7 Hz, 1H), 2.99 (d, J=7.6Hz, 1H), 2.80 (d, J=4.8 Hz, 3H), 2.69-2.55 (m, 2H), 2.36-2.24 (m, 2H),1.98-1.89 (m, 2H), 1.83-1.76 (m, 2H), 1.47 (d, J=9.6 Hz, 1H).

LC/MS, m/z=303 [M+H]⁺ (Calc: 302).

(b) Compound 77 was prepared in an analogous manner from Compound 73.

Compound 77 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.24 (s, 1H), 9.02 (bs, 1H),7.06 (s, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.66 (d, J=2.5 Hz, 1H), 6.61 (s,1H), 6.58 (dd, J=8.1, 2.5 Hz, 1H), 5.72 (s, 1H), 3.72 (d, J=4.7 Hz, 1H),3.25 (d, J=19.3 Hz, 1H), 3.12-2.94 (m, 4H), 2.78 (d, J=4.7 Hz, 3H),2.56-2.53 (m, 1H), 2.31-2.13 (m, 3H), 1.93-1.84 (m, 2H), 1.42 (d, J=9.1Hz, 1H); LC/MS, m/z=303 [M+H]⁺ (Calc: 302).

Example 20 Preparation of Compounds 118, 119, 122, and 123

(a) N-Phenyl-bis(trifluoromethanesulfonimide) (4.45 g, 12.45 mmol) wasadded to Compound 0 (3.78 g, 8.3 mmol, prepared by a method that isanalogous to those described above) and Cs₂CO₃ (8.11 g, 24.9 mmol) in 45mL THF and the solution was stirred at 60° C. for 15 h. The reactionmixture was concentrated and DCM was added, washed with 1M NaOH, driedwith Na₂SO₄ and concentrated. Purification by MPLC (0-10% MeOH/DCM) ledto the isolation of Compound P as a yellow oil (2.88 g, 59%, mixture ofamide diastereomers). LC/MS, m/z=588 [M+H]⁺ (Calc: 587).

(b) PdCl₂(dppf) (110 mg, 0.15 mmol) was added to a solution of CompoundP (1.76 g, 3 mmol), zinc cyanide (211 mg, 1.8 mmol), and zinc dust (49mg, 0.75 mmol) in 15 mL DMF and the solution was heated at 120° C. for15.5 h. The solution was cooled and sparged with nitrogen for 5 minPdCl₂(dppf) (110 mg, 0.15 mmol) was added and the solution was heated at120° C. for 8 h. PdCl₂(dppf) (110 mg, 0.15 mmol), zinc cyanide (211 mg,1.8 mmol), and zinc dust (49 mg, 0.75 mmol) were added and the solutionheated at 120° C. for 24 h. Additional PdCl₂(dppf) (110 mg, 0.15 mmol),zinc cyanide (211 mg, 1.8 mmol), and zinc dust (49 mg, 0.75 mmol) wereadded and the solution heated at 120° C. for 24 h. The reaction mixturewas concentrated and purified by MPLC (0-20% MeOH/DCM) to yield CompoundQ (1.88 g, 88%). A portion was purified by preparatory HPLC [0-40%MeCN/H₂O (0.01% TFA)] to yield Compound 122 and Compound 123 as theirbis-TFA salts.

In a similar manner, the following compounds were synthesized:

Compound 84: LC/MS, m/z=456.3 [M+H]⁺ (Calc: 455.3).

Compound 85: LC/MS, m/z=470.2 [M+H]⁺ (Calc: 469.3).

Compound 91: LC/MS, m/z=470.2 [M+H]⁺ (Calc: 469.3).

Compound 93: LC/MS, m/z=456.20 [M+H]⁺ (Calc: 455.59).

Compound 122 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.71 (br. s., 1H), 8.84(br. s., 1H), 8.05 (br. s., 1H), 7.86 (s, 1H), 7.64 (dd, J=8.0, 1.5 Hz,1H), 7.34 (d, J=8.1 Hz, 1H), 6.04 (s, 1H), 4.15 (d, J=5.0 Hz, 1H), 3.97(d, J=11.8 Hz, 2H), 3.67-3.18 (m, 7H, overlapped with water), 3.13-2.96(m, 7H), 2.91-2.80 (m, 1H), 2.63 (d, J=13.5 Hz, 1H), 2.39-2.11 (m, 4H),2.01-1.91 (m, 1H), 1.81 (dd, J=13.3, 8.6 Hz, 1H), 1.57 (d, J=12.5 Hz,1H), 1.08 (br. s., 1H), 0.74-0.65 (m, 1H), 0.65-0.56 (m, 1H), 0.54-0.38(m, 2H). LC/MS, m/z=465 [M+H]⁺ (Calc: 464).

Compound 123 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.86 (br. s., 1H), 8.86(br. s., 1H), 8.32 (br. s., 1H), 8.01 (s, 1H), 7.72 (dd, J=8.0, 1.5 Hz,1H), 7.39 (d, J=8.1 Hz, 1H), 6.33 (br. s., 1H), 4.17 (d, J=4.8 Hz, 1H),3.97 (br. s., 2H), 3.72-3.25 (m, 9H, overlapped with water), 3.24-3.06(m, 5H), 3.02 (d, J=12.7 Hz, 1H), 2.93-2.84 (m, 1H), 2.76 (dd, J=12.6,8.2 Hz, 1H), 2.42-2.31 (m, 1H), 2.29-2.14 (m, 1H), 2.08-2.02 (m, 1H),1.95 (d, J=13.1 Hz, 1H), 1.84-1.73 (m, 1H), 1.59 (d, J=11.7 Hz, 1H),1.07 (br. s., 1H), 0.73-0.65 (m, 1H), 0.64-0.55 (m, 1H), 0.52-0.32 (m,2H) LC/MS, m/z=465 [M+H]⁺ (Calc: 464).

(c) Hydrido(dimethylphosphinous acid-kP)[Hydrogenbis(dimethyl-phosphinito-kP)]platinum (II) (0.041 g, 0.097 mmol) wasadded to Compound Q (0.9 g, 1.9 mmol) in 10 mL of 1:1 EtOH/H₂O. Thesolution was heated at reflux for 2.5 h and concentrated. Purificationby MPLC (0-20% MeOH/DCM) followed by preparatory HPLC [0-40% MeCN/H₂O(0.01% TFA)] to yield Compound 118 and Compound 119 as their bis-TFAsalts.

Compound 118 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.69 (br. s., 1H), 8.81(br. s., 1H), 8.01 (t, J=5.3 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.69(dd, J=8.0, 1.4 Hz, 1H), 7.38 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 5.96 (s,1H), 4.14 (d, J=4.7 Hz, 1H), 3.95 (d, J=11.8 Hz, 2H), 3.71-3.24 (m, 6H,overlapped with water), 3.23-3.12 (m, 2H), 3.10-2.92 (m, 7H), 2.86 (d,J=7.2 Hz, 1H), 2.70-2.63 (m, 1H), 2.39-2.14 (m, 2H), 2.00-1.86 (m, 2H),1.51 (d, J=11.2 Hz, 1H), 1.14-1.02 (m, 1H), 0.75-0.65 (m, 1H), 0.65-0.56(m, 1H), 0.54-0.38 (m, 2H). LC/MS, m/z=483 [M+H]⁺ (Calc: 482).

Compound 119 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.79 (br. s., 1H), 8.84(br. s., 1H), 8.33 (t, J=5.3 Hz, 1H), 8.04-7.93 (m, 2H), 7.75 (dd,J=8.0, 1.5 Hz, 1H), 7.39 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.30 (br. s.,1H), 4.17 (d, J=5.2 Hz, 1H), 3.99 (d, J=11.6 Hz, 2H), 3.45-3.26 (m, 8H,overlapped with water), 3.23-3.06 (m, 5H), 3.01 (d, J=12.3 Hz, 1H),2.91-2.82 (m, 1H), 2.78 (dd, J=12.3, 8.1 Hz, 1H), 2.60-2.54 (m, 1H),2.44-2.34 (m, 1H), 2.29-2.16 (m, 1H), 2.13-2.04 (m, 1H), 1.97-1.90 (m,1H), 1.87-1.79 (m, 1H), 1.56 (d, J=12.1 Hz, 1H), 1.13-1.02 (m, 1H),0.76-0.65 (m, 1H), 0.65-0.55 (m, 1H), 0.52-0.37 (m, 2H). LC/MS, m/z=483[M+H]⁺ (Calc: 482).

The following compounds were prepared in an analogous fashion from theappropriate phenol:

Compound 120 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.83 (br. s., 1H), 8.17 (t,J=6.0 Hz, 1H), 7.86 (d, J=1.1 Hz, 1H), 7.65 (dd, J=8.0, 1.5 Hz, 1H),7.35 (d, J=8.0 Hz, 1H), 7.10 (d, J=7.9 Hz, 2H), 6.96 (d, J=8.0 Hz, 2H),5.99 (s, 1H), 4.17-3.98 (m, 4H), 3.51 (d, J=23.0 Hz, 1H), 3.44-3.31 (m,2H, overlapped with water), 3.15-2.94 (m, 2H), 2.90-2.79 (m, 1H), 2.63(d, J=15.6 Hz, 1H), 2.36-2.28 (m, 2H), 2.26 (s, 3H), 2.25-2.09 (m, 1H),2.03-1.92 (m, 1H), 1.90-1.82 (m, 1H), 1.58 (d, J=12.8 Hz, 1H), 1.08 (br.s., 1H), 0.74-0.65 (m, 1H), 0.64-0.56 (m, 1H), 0.53-0.37 (m, 2H). LC/MS,m/z=456 [M+H]⁺ (Calc: 455).

Compound 121 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.81 (br. s., 1H), 8.57 (t,J=5.9 Hz, 1H), 7.96 (d, J=1.3 Hz, 1H), 7.64 (dd, J=8.0, 1.5 Hz, 1H),7.31 (d, J=8.1 Hz, 1H), 7.12-7.01 (m, 4H), 6.62 (s, 1H), 4.27-4.10 (m,3H), 3.53-3.19 (m, 3H, overlapped with water), 2.94 (d, J=13.3 Hz, 1H),2.78 (dd, J=12.8, 8.4 Hz, 2H), 2.58 (d, J=10.3 Hz, 1H), 2.37-2.23 (m,2H), 2.21 (s, 3H), 2.13 (d, J=13.2 Hz, 1H), 1.95 (dd, J=13.0, 8.6 Hz,1H), 1.87-1.67 (m, 2H), 1.52 (d, J=12.2 Hz, 1H), 1.06-0.95 (m, 1H),0.67-0.58 (m, 1H), 0.58-0.48 (m, 1H), 0.43-0.28 (m, 2H). LC/MS, m/z=456[M+H]⁺ (Calc: 455).

Compound 117 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.80 (br. s., 1H), 8.11 (t,J=5.9 Hz, 1H), 7.93 (s, 2H), 7.71 (dd, J=8.1, 1.3 Hz, 1H), 7.36 (s, 1H),7.22 (d, J=8.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H),5.91 (s, 1H), 4.17-3.97 (m, 3H), 3.38-3.17 (m, 3H, overlapped withwater), 3.15-3.05 (m, 1H), 3.00 (d, J=12.8 Hz, 1H), 2.87-2.79 (m, 1H),2.73-2.66 (m, 1H), 2.41-2.29 (m, 2H), 2.26 (s, 3H), 2.23-2.11 (m, 1H),1.94 (d, J=8.7 Hz, 2H), 1.52 (d, J=11.7 Hz, 1H), 1.14-1.04 (m, 1H),0.75-0.65 (m, 1H), 0.64-0.55 (m, 1H), 0.54-0.38 (m, 2H). LC/MS, m/z=474[M+H]⁺ (Calc: 473).

Compound 116 TFA salt: ¹H NMR (DMSO-d₆) δ: 8.85 (br. s., 1H), 8.69 (t,J=5.9 Hz, 1H), 8.02-7.95 (m, 2H), 7.74 (dd, J=8.1, 1.4 Hz, 1H), 7.37 (s,1H), 7.26 (d, J=8.1 Hz, 1H), 7.17-7.09 (m, 4H), 6.72 (s, 1H), 4.33-4.15(m, 3H), 3.53-3.44 (m, 3H), 3.01 (d, J=11.2 Hz, 1H), 2.92-2.80 (m, 2H),2.73-2.63 (m, 1H), 2.45-2.36 (m, 1H), 2.28 (s, 3H), 2.26-2.16 (m, 1H),2.04 (dd, J=12.9, 8.5 Hz, 1H), 1.89-1.82 (m, 2H), 1.55 (d, J=11.3 Hz,1H), 1.12-1.04 (m, 1H), 0.75-0.66 (m, 1H), 0.65-0.56 (m, 1H), 0.51-0.37(m, 2H). LC/MS, m/z=474 [M+H]⁺ (Calc: 473).

Example 21

The following compounds were prepared by methods analogous to thosedescribed above:

Compound 79: ¹H NMR (DMSO-d₆) δ: 9.10 (s., 1H), 8.36-8.33 (d, 1H),7.86-7.83 (m, 1H), 7.52-7.39 (m, 3H), 6.90 (d, 1H), 6.71 (d, 1H), 6.56(dd, 1H), 4.58 (s, 1H), 3.96-3.87 (m, 1H), 3.31 (s, 1H), 3.22-3.16 (m,1H), 2.99 (dd, 1H), 2.77 (d, 1H), 2.57-2.47 (m, 2H), 2.40-2.30 (m, 2H),2.15-1.99 (m, 3H), 1.88-1.82 (m, 1H), 1.53-1.49 (d, 1H), 1.30 (m, 1H),0.88-0.82 (m, 1H), 0.48-0.43 (m, 2H), 0.15-0.07 (m, 2H). LC/MS,m/z=419.2 [M+H]⁺ (Calc: 418.2).

Compound 80: δ: 9.46 (s, 1H), 8.85 (d, 1H), 7.43 (d, 2H), 7.02-7.00 (d,1H), 6.75 (d, 1H), 6.70-6.67 (dd, 1H), 6.56 (dd, 1H), 6.16 (s, 1H), 4.09(d, 1H), 4.03-4.00 (m, 2H), 3.92 (s, 1H), 3.57 (br, s, 2H), 3.36-3.27(m, 2H), 3.12-3.00 (m, 2H), 2.85-2.79 (m, 1H), 2.53 (d, 1H), 2.43-2.36(m, 1H), 2.33-2.28 (m, 2H), 2.26-2.17 (m, 1H), 1.84-1.79 (dd, 1H),1.51-1.47 (d, 1H), 1.17-1.04 (m, 1H), 0.70-0.55 (m, 2H), 0.51-0.40 (m,2H). LC/MS, m/z=405.3 [M+H]⁺ (Calc: 404.3).

Compound 81: δ: 9.98 (s, 1H), 9.51-9.36 (d, 1H), 8.87-8.72 (d, 1H),7.45-7.16 (m, 6H), 7.08-6.97 (2H), 6.86 (s, 1H), 6.66 (m, 1H), 6.17 (s,1H), 5.67 (br, s, 1H), 4.10-3.71 (m, 6H), 3.38-3.01 (m, 3H), 2.83 (m,2H), 2.39-2.25 (m, 3H), 2.16-2.07 (m, 1H), 1.86 (m, 1H), 1.67-1.48 (m,2H), 1.08 (m, 1H), 0.66-0.58 (d, 2H), 0.48-0.41 (d, 2H). LC/MS,m/z=495.3 [M+H]⁺ (Calc: 494.3).

Compound 82: ¹H NMR (DMSO-d₆) δ: 9.27 (s, 1H), 8.78 (s, 1H), 7.74-7.72(m, 1H), 7.57-7.55 (m, 2H), 7.49-7.45 (m, 1H), 7.39-7.35 (m, 1H), 7.01(d, 1H), 6.78-6.75 (d, 1H), 6.68-6.65 (dd, 1H), 4.55 (m, 1H), 4.07 (m,1H), 3.82 (br, 1H), 3.36-3.30 (m, 2H), 3.16-3.10 (m, 1H), 2.99 (dd, 1H),2.83-2.79 (m, 1H), 2.51-2.50 (m, 2H), 2.47-2.23 (m, 3H), 1.93-1.88 (m,1H), 1.47-1.44 (m, 1H), 1.09 (m, 1H), 0.72-0.55 (m, 2H), 0.52-0.40 (m,2H). LC/MS, m/z=419.2 [M+H]⁺ (Calc: 418.2).

Compound 83: ¹H NMR (DMSO-d₆) δ: 9.39 (s, 1H), 8.78 (s, 1H), 8.34 (s,1H), 7.31-7.29 (d, 2H), 7.19 (m, 2H), 7.03-7.01 (d, 1H), 6.88-6.85 (m,1H), 6.78 (d, 1H), 6.68-6.66 (dd, 1H), 5.93 (s, 1H), 5.66-5.64 (d, 1H),4.56-4.48 (m, 1H), 4.02 (m, 1H), 3.36-3.27 (m, 2H), 3.19-3.13 (m, 1H),3.00-2.97 (d, 1H), 2.85-2.79 (1H), 2.46-2.40 (m, 1H), 2.33-2.26 (m, 2H),2.15-2.12 (d, 1H), 1.46-1.38 (m, 2H), 1.07 (m, 1H), 0.71-0.56 (m, 2H),0.50-0.39 (m, 2H). LC/MS, m/z=434.2 [M+H]⁺ (Calc: 433.2).

Compound 86: LC/MS, m/z=488.3 [M+H]⁺ (Calc: 487.3).

Compound 88: LC/MS, m/z=480.3 [M+H]⁺ (Calc: 479.3).

Compound 95: ¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 7.77-7.70 (m, 2H),7.67-7.53 (m, 3H), 7.44 (d, J=5.3 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.63(d, J=2.2 Hz, 1H), 6.53 (dd, J=8.3, 2.3 Hz, 1H), 4.31 (d, J=2.0 Hz, 1H),3.70-3.58 (m, 1H), 3.10 (d, J=4.8 Hz, 1H), 2.96 (d, J=18.0 Hz, 1H), 2.55(dd, J=18.5, 5.5 Hz, 1H), 2.39-2.16 (m, 3H), 2.12-2.00 (m, 1H),2.00-1.87 (m, 1H), 1.84-1.72 (m, 1H), 1.65-1.53 (m, 1H), 1.51-1.40 (m,1H), 1.17 (d, J=12.3 Hz, 1H), 0.85-0.71 (m, 1H), 0.48-0.35 (m, 2H),0.13-0.00 (m, 2H). LC/MS, m/z=455.1 [M+H]⁺ (Calc: 454.2).

Compound 96 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.36 (br. s., 1H), 8.75 (br.s., 1H), 7.28-7.19 (m, J=8.5, 7.4 Hz, 2H), 7.04-6.91 (m, 3H), 6.87-6.77(m, 2H), 6.67 (dd, J=8.3, 2.4 Hz, 1H), 6.32 (s, 1H), 4.10 (d, J=4.7 Hz,1H), 3.75-3.54 (m, 4H overlapped with water), 3.36-3.26 (m, 3H),3.21-3.06 (m, 6H), 2.99 (d, J=10.0 Hz, 1H), 2.89-2.79 (m, 1H), 2.60 (dd,J=12.6, 8.3 Hz, 1H), 2.41-2.23 (m, 2H), 2.09 (dd, J=12.8, 8.6 Hz, 1H),1.98-1.92 (m, 2H), 1.49 (d, J=10.8 Hz, 1H), 1.07 (br. s., 1H), 0.73-0.64(m, 1H), 0.63-0.54 (m, 1H), 0.51-0.44 (m, 1H), 0.44-0.35 (m, 1H). LC/MS,m/z=488 [M+H]⁺ (Calc: 487).

Compound 97 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.30 (s, 1H), 8.99 (br. s.,1H), 8.64 (t, J=5.9 Hz, 1H), 7.13-7.02 (m, 4H), 6.93 (d, J=8.3 Hz, 1H),6.70 (d, J=2.3 Hz, 1H), 6.59 (dd, J=8.3, 2.4 Hz, 1H), 6.49 (s, 1H), 4.18(t, J=5.2 Hz, 2H), 3.74 (d, J=4.9 Hz, 1H), 3.23 (d, J=19.5 Hz, 1H), 3.05(dd, J=19.8, 5.7 Hz, 1H), 2.92 (d, J=8.7 Hz, 1H), 2.73 (d, J=5.0 Hz,3H), 2.68-2.58 (m, 1H), 2.54 (dd, J=12.5, 8.4 Hz, 1H), 2.28-2.16 (m,5H), 1.89 (dd, J=12.5, 8.2 Hz, 1H), 1.82-1.70 (m, 2H), 1.41 (d, J=10.1Hz, 1H). LC/MS, m/z=407 [M+H]⁺ (Calc: 406).

Compound 98 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.25 (s, 1H), 9.18 (s, 1H),9.00 (s, 1H), 8.95 (br. s, 1H), 7.93 (t, J=5.8 Hz, 1H), 6.89 (d, J=8.3Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.58 (d, J=8.3 Hz, 1H), 6.54 (dd,J=8.3, 2.3 Hz, 1H), 6.14 (d, J=2.3 Hz, 1H), 6.07 (dd, J=8.2, 2.4 Hz,1H), 6.10-6.04 (m, 1H), 5.66 (s, 1H), 3.88 (dd, J=5.6, 2.1 Hz, 2H), 3.65(d, J=3.9 Hz, 1H), 3.19 (d, J=19.2 Hz, 1H), 3.03 (br. s., 2H), 2.92 (d,J=9.6 Hz, 1H), 2.71 (d, J=5.0 Hz, 3H), 2.48-2.45 (m, 1H), 2.29-2.07 (m,3H), 1.84 (dd, J=8.7, 4.6 Hz, 2H), 1.36 (d, J=10.1 Hz, 1H). LC/MS,m/z=425 [M+H]⁺ (Calc: 424).

Compound 99 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.26 (br. s., 1H), 9.04 (br.s., 1H), 8.22 (t, J=5.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.39 (d, J=1.9Hz, 1H), 7.03-6.91 (m, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.61 (dd, J=8.3, 2.4Hz, 1H), 5.77 (s, 1H), 4.13 (d, J=5.9 Hz, 2H), 3.74 (d, J=3.7 Hz, 1H),3.27 (d, J=19.0 Hz, 1H), 3.16-2.95 (m, 3H), 2.78 (d, J=5.0 Hz, 3H), 2.56(dd, J=13.1, 2.8 Hz, 1H), 2.34-2.14 (m, 3H), 2.02-1.85 (m, 2H), 1.44 (d,J=10.0 Hz, 1H). LC/MS, m/z=461 [M+H]⁺ (Calc: 460).

Compound 100 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.25 (br. s., 1H), 9.04 (br.s., 1H), 7.68 (t, J=5.6 Hz, 1H), 7.30-7.22 (m, 2H), 7.22-7.16 (m, 1H),7.09 (d, J=7.0 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H),6.60 (dd, J=8.3, 2.4 Hz, 1H), 5.75 (br. s., 2H), 3.73 (d, J=3.7 Hz, 1H),3.26 (dd, J=17.6, 1.0 Hz, 1H), 3.23-3.06 (m, 3H), 3.06-2.91 (m, 2H),2.78 (d, J=5.0 Hz, 3H), 2.61-2.55 (m, 2H), 2.34-2.20 (m, 2H), 2.15 (t,J=12.7 Hz, 1H), 1.93-1.80 (m, 2H), 1.42 (d, J=9.4 Hz, 1H). LC/MS,m/z=407 [M+H]⁺ (Calc: 406).

Compound 101 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.31 (br. s., 1H), 8.99 (br.s., 1H), 8.67 (t, J=5.9 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.43 (d, J=1.9Hz, 1H), 7.17 (dd, J=8.3, 2.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.71 (d,J=2.3 Hz, 1H), 6.60 (dd, J=8.3, 2.3 Hz, 1H), 6.25 (s, 1H), 4.23 (d,J=6.3 Hz, 2H), 3.72 (d, J=4.9 Hz, 1H), 3.22 (d, J=19.5 Hz, 1H),3.13-3.01 (m, 1H), 2.92 (d, J=8.5 Hz, 1H), 2.73 (d, J=4.9 Hz, 3H),2.69-2.49 (m, 2H), 2.34-2.13 (m, 2H), 1.92 (dd, J=12.3, 8.3 Hz, 1H),1.79 (d, J=6.7 Hz, 2H), 1.41 (d, J=9.7 Hz, 1H). LC/MS, m/z=461 [M+H]⁺(Calc: 460).

Compound 102 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.35 (s, 1H), 9.04 (br. s.,1H), 8.25 (t, J=5.7 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.77 (d, J=2.4 Hz,1H), 6.68 (s, 1H), 6.66 (dd, J=8.3, 2.3 Hz, 1H), 3.81 (d, J=3.5 Hz, 1H),3.31-3.25 (m, 1H, overlapped with water), 3.11 (dd, J=19.3, 5.4 Hz, 1H),3.02-2.84 (m, 4H), 2.80 (d, J=4.9 Hz, 3H), 2.59 (dd, J=12.4, 8.4 Hz,1H), 2.38-2.26 (m, 2H), 1.95-1.63 (m, 4H), 1.47 (d, J=9.1 Hz, 1H), 0.84(d, J=6.7 Hz, 6H). LC/MS, m/z=359 [M+H]⁺ (Calc: 358).

Compound 103 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.30 (br. s., 1H), 9.05 (br.s., 1H), 8.19 (t, J=5.8 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.35 (dd,J=8.3, 2.1 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.70(d, J=2.3 Hz, 1H), 6.63 (dd, J=8.2, 2.3 Hz, 1H), 5.79 (s, 1H), 4.15 (d,J=5.8 Hz, 2H), 3.75 (d, J=4.2 Hz, 1H), 3.28 (d, J=19.4 Hz, 1H),3.19-2.96 (m, 3H), 2.79 (d, J=5.0 Hz, 3H), 2.60 (dd, J=12.9, 2.6 Hz,1H), 2.36-2.15 (m, 3H), 2.04-1.89 (m, 2H), 1.45 (d, J=9.8 Hz, 1H).LC/MS, m/z=461 [M+H]⁺ (Calc: 460).

Compound 104 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.20 (br. s., 1H), 8.97 (br.s., 1H), 8.02 (t, J=5.9 Hz, 1H), 7.01 (d, J=7.8 Hz, 2H), 6.93-6.84 (m,3H), 6.62 (d, J=2.3 Hz, 1H), 6.55 (dd, J=8.3, 2.4 Hz, 1H), 5.68 (br. s.,1H), 4.03 (d, J=5.9 Hz, 2H), 3.67 (d, J=3.9 Hz, 1H), 3.25-3.15 (m, 1H),3.08-2.89 (m, 3H), 2.71 (d, J=5.0 Hz, 3H), 2.48 (dd, J=13.1, 2.9 Hz,1H), 2.26-2.10 (m, 7H), 1.86 (d, J=9.1 Hz, 2H), 1.37 (d, J=9.7 Hz, 1H).LC/MS, m/z=407 [M+H]⁺ (Calc: 406).

Compound 105 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.26 (s, 1H), 9.04 (br. s.,1H), 8.13 (t, J=5.9 Hz, 1H), 7.31-7.25 (m, 2H), 7.23-7.16 (m, 1H), 7.05(d, J=7.2 Hz, 2H), 6.97 (d, J=8.3 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 6.62(dd, J=8.3, 2.3 Hz, 1H), 5.75 (s, 1H), 4.15 (d, J=5.8 Hz, 2H), 3.74 (d,J=4.2 Hz, 1H), 3.27 (d, J=19.4 Hz, 1H), 3.15-3.05 (m, 2H), 2.99 (d,J=8.5 Hz, 1H), 2.78 (d, J=5.0 Hz, 3H), 2.57 (dd, J=12.9, 2.9 Hz, 1H),2.35-2.18 (m, 3H), 1.94 (d, J=8.9 Hz, 2H), 1.44 (d, J=9.6 Hz, 1H).LC/MS, m/z=393 [M+H]⁺ (Calc: 392).

Compound 106 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.37 (s, 1H), 9.07 (br. s.,1H), 8.75 (t, J=5.8 Hz, 1H), 7.36-7.30 (m, 2H), 7.30-7.21 (m, 3H), 7.00(d, J=8.4 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.3, 2.3 Hz, 1H),6.53 (s, 1H), 4.31 (t, J=5.4 Hz, 2H), 3.81 (d, J=5.1 Hz, 1H), 3.30 (d,J=19.9 Hz, 1H), 3.17-3.08 (m, 1H), 2.99 (d, J=8.4 Hz, 1H), 2.80 (d,J=4.1 Hz, 3H), 2.76-2.66 (m, 1H), 2.62 (dd, J=12.4, 8.5 Hz, 1H),2.38-2.24 (m, 2H), 1.98 (dd, J=12.6, 8.2 Hz, 1H), 1.91-1.79 (m, 2H),1.48 (d, J=10.2 Hz, 1H). LC/MS, m/z=393 [M+H]⁺ (Calc: 392).

Compound 107 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.30 (br. s., 1H), 8.98 (br.s., 1H), 8.63 (t, J=5.7 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.37 (dd,J=8.3, 2.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.70(d, J=2.4 Hz, 1H), 6.60 (dd, J=8.3, 2.4 Hz, 1H), 6.22 (s, 1H), 4.36-4.19(m, 2H), 3.72 (d, J=5.0 Hz, 1H), 3.22 (d, J=19.5 Hz, 1H), 3.17-2.99 (m,1H), 2.98-2.82 (m, 1H), 2.72 (d, J=5.0 Hz, 3H), 2.69-2.60 (m, 1H), 2.54(dd, J=12.4, 8.2 Hz, 1H), 2.34-2.13 (m, 3H), 1.93 (dd, J=12.5, 8.6 Hz,1H), 1.80 (d, J=6.8 Hz, 2H), 1.41 (d, J=9.5 Hz, 1H). LC/MS, m/z=461[M+H]⁺ (Calc: 460).

Compound 108 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (s, 1H), 8.97 (br. s.,1H), 8.28 (t, J=5.6 Hz, 1H), 7.25-7.19 (m, 2H), 7.17-7.11 (m, 3H), 6.92(d, J=8.3 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.59 (dd, J=8.3, 2.3 Hz, 1H),6.55 (s, 1H), 3.73 (d, J=4.8 Hz, 1H), 3.33-3.15 (m, 3H, overlapped bywater), 3.09-3.00 (m, 1H), 2.92 (d, J=7.9 Hz, 1H), 2.72 (d, J=5.0 Hz,3H), 2.65 (t, J=7.3 Hz, 2H), 2.58-2.45 (m, 2H), 2.29-2.16 (m, 2H),1.85-1.62 (m, 3H), 1.40 (d, J=9.5 Hz, 1H). LC/MS, m/z=407 [M+H]⁺ (Calc:406).

Compound 109 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.39 (br. s., 1H), 9.05 (br.s., 1H), 8.55 (d, J=7.3 Hz, 1H), 7.85-7.80 (m, 2H), 7.57-7.51 (m, 1H),7.51-7.45 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 6.70(dd, J=8.3, 2.3 Hz, 1H), 6.36 (s, 1H), 3.97-3.85 (m, 1H), 3.78 (d, J=4.7Hz, 1H), 3.34-3.26 (m, 1H), 3.24-3.13 (m, 1H), 3.01 (d, J=8.1 Hz, 1H),2.81 (d, J=5.0 Hz, 3H), 2.59 (dd, J=12.4, 7.6 Hz, 1H), 2.42-2.30 (m,2H), 2.28-2.15 (m, 2H), 1.72 (dd, J=14.9, 3.1 Hz, 1H), 1.49 (d, J=9.7Hz, 1H). LC/MS, m/z=379 [M+H]⁺ (Calc: 378).

Compound 110 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.26 (br. s., 1H), 9.08 (br.s., 1H), 7.72 (d, J=5.9 Hz, 1H), 7.58-7.53 (m, 2H), 7.50-7.44 (m, 1H),7.41-7.33 (m, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.75 (d, J=2.3 Hz, 1H), 6.66(dd, J=8.3, 2.3 Hz, 1H), 5.85 (s, 1H), 4.58-4.48 (m, 1H), 3.74 (d, J=3.9Hz, 1H), 3.32 (d, J=19.2 Hz, 1H), 3.13-2.97 (m, 2H), 2.79 (d, J=5.0 Hz,3H), 2.46-2.20 (m, 5H), 1.87 (dd, J=13.5, 7.7 Hz, 1H), 1.45 (d, J=9.1Hz, 1H). LC/MS, m/z=379 [M+H]⁺ (Calc: 378).

Compound 111 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.23 (s, 1H), 9.04 (br. s.,1H), 6.95 (d, J=8.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.58 (dd, J=8.3,2.3 Hz, 1H), 5.75 (s, 1H), 3.73 (d, J=4.7 Hz, 1H), 3.64-3.30 (m, 9H,overlapped with water), 3.26 (d, J=19.7 Hz, 1H), 3.14-3.07 (m, 1H), 2.99(d, J=6.5 Hz, 1H), 2.78 (d, J=5.0 Hz, 3H), 2.44 (dd, J=12.8, 3.2 Hz,1H), 2.26 (d, J=10.9 Hz, 3H), 2.02 (dd, J=12.9, 9.5 Hz, 1H), 1.91-1.83(m, 1H), 1.44 (d, J=10.1 Hz, 1H). LC/MS, m/z=373 [M+H]⁺ (Calc: 372).

Compound 112 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.73 (br. s., 1H), 9.26(s, 1H), 9.03 (br. s., 1H), 7.97 (br. s., 1H), 6.95 (d, J=8.3 Hz, 1H),6.65 (d, J=2.3 Hz, 1H), 6.60 (dd, J=8.2, 2.3 Hz, 1H), 5.79 (s, 1H), 3.96(d, J=12.6 Hz, 2H), 3.74 (d, J=3.9 Hz, 1H), 3.65-3.55 (m, 2H), 3.33-3.17(m, 3H, overlapped with water), 3.12-2.92 (m, 8H), 2.79 (d, J=5.0 Hz,3H), 2.57-2.54 (m, 1H), 2.30-2.16 (m, 3H), 1.91 (d, J=8.6 Hz, 2H), 1.44(d, J=9.1 Hz, 1H). LC/MS, m/z=416 [M+H]⁺ (Calc: 415).

Compound 113 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.23 (s, 1H), 9.17 (br.s., 1H), 9.04 (br. s., 1H), 6.95 (d, J=8.3 Hz, 1H), 6.63 (d, J=2.3 Hz,1H), 6.59 (dd, J=8.2, 2.3 Hz, 1H), 5.80 (s, 1H), 3.74 (br. s., 1H),3.60-3.22 (m, 4H, overlapped with water), 3.21-3.03 (m, 3H), 3.00 (s,3H), 2.86 (d, J=4.2 Hz, 1H), 2.79 (d, J=5.0 Hz, 3H), 2.74 (t, J=4.6 Hz,6H), 2.42 (dd, J=12.8, 3.1 Hz, 1H), 2.36-2.30 (m, 1H), 2.27 (d, J=13.3Hz, 2H), 2.06 (dd, J=12.7, 9.1 Hz, 1H), 1.86 (dd, J=13.0, 8.1 Hz, 1H),1.44 (d, J=9.6 Hz, 1H). LC/MS, m/z=388 [M+H]⁺ (Calc: 387).

Compound 114 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.21 (s, 1H), 9.01 (br. s.,1H), 7.60 (t, J=5.6 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.64 (d, J=2.3 Hz,1H), 6.58 (dd, J=8.2, 2.3 Hz, 1H), 5.71 (s, 1H), 4.57 (br. s., 1H), 3.72(d, J=3.7 Hz, 1H), 3.33-3.19 (m, 3H, overlapped with water), 3.13-2.89(m, 5H), 2.77 (d, J=5.0 Hz, 3H), 2.46 (dd, J=10.3, 2.9 Hz, 1H), 2.24 (s,3H), 1.88 (d, J=8.7 Hz, 2H), 1.42 (d, J=9.7 Hz, 1H). LC/MS, m/z=347[M+H]⁺ (Calc: 346).

Compound 115 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.38 (br. s., 1H), 9.05 (br.s., 1H), 8.33 (t, J=5.6 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.76 (d, J=2.4Hz, 1H), 6.74 (s, 1H), 6.66 (dd, J=8.3, 2.3 Hz, 1H), 4.73 (br. s., 1H),3.81 (d, J=4.8 Hz, 1H), 3.41 (t, J=5.9 Hz, 2H), 3.29 (d, J=19.4 Hz, 1H),3.20-3.06 (m, 3H), 2.99 (d, J=8.3 Hz, 1H), 2.80 (d, J=4.9 Hz, 3H),2.74-2.64 (m, 1H), 2.58 (dd, J=12.6, 8.6 Hz, 1H), 2.40-2.22 (m, 2H),1.95-1.71 (m, 3H), 1.47 (d, J=10.0 Hz, 1H). LC/MS, m/z=347 [M+H]⁺ (Calc:346).

Compound 124 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.17 (s, 1H), 8.96 (s, 1H),8.65 (br. s., 1H), 8.55 (s, 1H), 8.08 (t, J=5.9 Hz, 1H), 6.88 (d, J=8.3Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.58-6.51 (m, 2H), 6.48 (t, J=7.7 Hz,1H), 6.29 (dd, J=7.6, 1.4 Hz, 1H), 5.75 (s, 1H), 4.05-3.93 (m, 3H),3.27-3.16 (m, 2H, overlapped with water), 3.12-3.00 (m, 2H), 2.91 (d,J=10.6 Hz, 1H), 2.78-2.70 (m, 1H), 2.50-2.45 (m, 1H, overlapped withDMSO), 2.29-2.09 (m, 3H), 1.93-1.80 (m, 2H), 1.37 (d, J=11.1 Hz, 1H),1.06-0.95 (m, 1H), 0.64-0.57 (m, 1H), 0.56-0.47 (m, 1H), 0.46-0.37 (m,1H), 0.37-0.29 (m, 1H). LC/MS, m/z=465 [M+H]⁺ (Calc: 464).

Compound 125 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.17 (br. s., 1H), 8.65 (br.s., 1H), 8.02 (t, J=5.6 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.07 (t, J=7.8Hz, 1H), 6.90-6.85 (m, 2H), 6.62 (d, J=2.3 Hz, 1H), 6.54 (dd, J=8.3, 2.4Hz, 1H), 5.76 (s, 1H), 4.09 (d, J=5.6 Hz, 2H), 3.99 (d, J=4.2 Hz, 1H),3.28-3.18 (m, 2H), 3.12-3.02 (m, 2H), 2.91 (d, J=9.9 Hz, 1H), 2.79-2.70(m, 1H), 2.49 (dd, J=13.0, 2.7 Hz, 1H), 2.32-2.11 (m, 6H), 1.89 (d,J=9.4 Hz, 2H), 1.38 (d, J=10.9 Hz, 1H), 1.07-0.96 (m, 1H), 0.65-0.56 (m,1H), 0.55-0.48 (m, 1H), 0.45-0.30 (m, 2H). LC/MS, m/z=481 [M+H]⁺ (Calc:480).

Compound 126 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.16 (s, 1H), 8.65 (br. s.,1H), 8.10 (t, J=5.9 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.11 (d, J=1.2 Hz,1H), 6.88 (d, J=8.4 Hz, 1H), 6.84 (dd, J=7.8, 1.4 Hz, 1H), 6.61 (d,J=2.3 Hz, 1H), 6.54 (dd, J=8.3, 2.4 Hz, 1H), 5.75 (s, 1H), 4.09-4.01 (m,2H), 3.99 (d, J=4.9 Hz, 1H), 3.27-3.17 (m, 2H, overlapped with water),3.10-2.99 (m, 2H), 2.91 (d, J=10.2 Hz, 1H), 2.78-2.70 (m, 1H), 2.50-2.46(m, 1H, overlapped with DMSO), 2.30-2.12 (m, 6H), 1.93-1.81 (m, 2H),1.38 (d, J=11.2 Hz, 1H), 1.06-0.94 (m, 1H), 0.66-0.56 (m, 1H), 0.56-0.47(m, 1H), 0.45-0.38 (m, 1H), 0.38-0.31 (m, 1H). LC/MS, m/z=481 [M+H]⁺(Calc: 480).

Compound 127 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.68 (s, 1H), 9.18 (s, 1H),8.65 (br. s., 1H), 7.96 (t, J=5.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.76(d, J=8.4 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.64-6.59 (m, 2H), 6.54 (dd,J=8.3, 2.3 Hz, 1H), 5.75 (s, 1H), 4.02 (d, J=5.7 Hz, 2H), 3.99 (d, J=4.6Hz, 1H), 3.28-3.18 (m, 2H, overlapped with water), 3.10-3.01 (m, 2H),2.91 (d, J=9.5 Hz, 1H), 2.79-2.70 (m, 1H), 2.49 (dd, J=13.1, 2.6 Hz,2H), 2.28-2.11 (m, 3H), 1.88 (d, J=8.8 Hz, 2H), 1.38 (d, J=11.2 Hz, 1H),1.07-0.96 (m, 1H), 0.65-0.57 (m, 1H), 0.57-0.47 (m, 1H), 0.46-0.38 (m,1H), 0.38-0.30 (m, 1H). LC/MS, m/z=483 [M+H]⁺ (Calc: 482).

Compound 128 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.93 (s, 1H), 9.16 (s, 1H),8.64 (br. s., 1H), 8.02 (t, J=5.9 Hz, 1H), 7.03 (d, J=1.9 Hz, 1H), 6.87(d, J=8.3 Hz, 1H), 6.83-6.74 (m, 2H), 6.61 (d, J=2.3 Hz, 1H), 6.53 (dd,J=8.3, 2.3 Hz, 1H), 5.74 (s, 1H), 4.01-3.92 (m, 3H), 3.27-3.17 (m, 2H,overlapped with water), 3.10-2.97 (m, 2H), 2.90 (d, J=9.9 Hz, 1H),2.78-2.69 (m, 1H), 2.49-2.45 (m, 1H), 2.29-2.10 (m, 3H), 1.92-1.79 (m,2H), 1.37 (d, J=11.3 Hz, 1H), 1.06-0.95 (m, 1H), 0.64-0.57 (m, 1H),0.56-0.48 (m, 1H), 0.46-0.38 (m, 1H), 0.37-0.30 (m, 1H). LC/MS, m/z=483[M+H]⁺ (Calc: 482).

Compound 129 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.23 (br. s., 1H), 8.70 (br.s., 1H), 7.67 (t, J=5.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4Hz, 2H), 6.95 (d, J=8.3 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 6.60 (dd,J=8.3, 2.3 Hz, 1H), 5.80 (s, 1H), 4.04 (d, J=4.3 Hz, 1H), 3.36-3.25 (m,2H), 3.16-3.07 (m, 3H), 3.04-2.94 (m, 2H), 2.85-2.77 (m, 1H), 2.64-2.55(m, 2H), 2.50-2.45 (m, 1H, overlapped with DMSO), 2.34-2.12 (m, 3H),1.93-1.83 (m, 2H), 1.43 (d, J=10.2 Hz, 1H), 1.14-1.04 (m, 1H), 0.72-0.64(m, 1H), 0.63-0.54 (m, 1H), 0.52-0.45 (m, 1H), 0.44-0.36 (m, 1H). LC/MS,m/z=481 [M+H]⁺ (Calc: 480).

Compound 130 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.23 (br. s., 1H), 8.71 (br.s., 1H), 7.71 (t, J=5.7 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.33 (dd,J=8.3, 2.1 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.67(d, J=2.3 Hz, 1H), 6.60 (dd, J=8.2, 2.3 Hz, 1H), 5.80 (s, 1H), 4.04 (d,J=4.1 Hz, 1H), 3.35-3.25 (m, 2H), 3.22-3.07 (m, 3H), 3.06-2.93 (m, 2H),2.85-2.76 (m, 1H), 2.75-2.65 (m, 2H), 2.49-2.46 (m, 1H, overlapped withDMSO), 2.34-2.11 (m, 3H), 1.93-1.81 (m, 2H), 1.43 (d, J=10.3 Hz, 1H),1.12-1.03 (m, 1H), 0.72-0.63 (m, 1H), 0.62-0.54 (m, 1H), 0.52-0.45 (m,1H), 0.44-0.37 (m, 1H). LC/MS, m/z=515 [M+H]⁺ (Calc: 514).

Compound 131 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.23 (br. s., 1H), 8.71 (br.s., 1H), 7.68 (t, J=5.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.40 (d, J=1.9Hz, 1H), 7.07 (dd, J=8.2, 2.0 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.65 (d,J=2.3 Hz, 1H), 6.59 (dd, J=8.2, 2.3 Hz, 1H), 5.80 (s, 1H), 4.04 (d,J=4.2 Hz, 1H), 3.35-3.24 (m, 2H), 3.20-3.09 (m, 3H), 3.09-2.93 (m, 3H),2.85-2.76 (m, 1H), 2.65-2.55 (m, 2H), 2.50-2.44 (m, 1H, overlapped withDMSO), 2.34-2.10 (m, 4H), 1.92-1.81 (m, 2H), 1.43 (d, J=10.4 Hz, 1H),1.13-1.04 (m, 1H), 0.72-0.64 (m, 1H), 0.63-0.54 (m, 1H), 0.52-0.46 (m,1H), 0.45-0.37 (m, 1H). LC/MS, m/z=515 [M+H]⁺ (Calc: 514).

Compound 132 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.52 (br. s., 1H), 9.17(s, 1H), 8.69 (br. s., 1H), 6.87 (d, J=7.8 Hz, 1H), 6.63 (d, J=37.2 Hz,1H), 6.52 (dd, J=8.3, 2.4 Hz, 1H), 5.83 (br. s., 1H), 4.34-4.20 (m, 1H),4.08-3.94 (m, 2H), 3.26-3.18 (m, 3H), 3.10-3.02 (m, 1H), 2.95-2.88 (m,1H), 2.82-2.70 (m, 3H), 2.54-2.46 (m, 1H), 2.37-2.11 (m, 4H), 2.07-1.96(m, 1H), 1.95-1.79 (m, 1H), 1.38 (d, J=11.7 Hz, 1H), 1.24-1.15 (m, 6H),1.07-0.96 (m, 1H), 0.65-0.58 (m, 1H), 0.57-0.48 (m, 1H), 0.46-0.39 (m,1H), 0.38-0.30 (m, 1H). LC/MS, m/z=454 [M+H]⁺ (Calc: 453).

Compound 133 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.38 (s, 1H), 9.15 (br.s., 1H), 8.73 (br. s., 1H), 8.36 (t, J=5.6 Hz, 1H), 6.99 (d, J=8.4 Hz,1H), 6.77 (d, J=2.3 Hz, 1H), 6.67 (dd, J=8.3, 2.4 Hz, 1H), 6.24 (s, 1H),4.09 (d, J=4.9 Hz, 1H), 3.36-3.27 (m, 2H, overlapped with water),3.20-3.06 (m, 4H), 3.01-2.79 (m, 4H), 2.63-2.53 (m, 3H), 2.39-2.23 (m,2H), 2.06-1.98 (m, 1H), 1.97-1.77 (m, 4H), 1.75-1.55 (m, 3H), 1.49 (d,J=10.3 Hz, 1H), 1.44-1.32 (m, 1H), 1.11-1.01 (m, 1H), 0.73-0.64 (m, 1H),0.64-0.54 (m, 1H), 0.50-0.35 (m, 2H). LC/MS, m/z=454 [M+H]⁺ (Calc: 453).

Compound 134 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 10.03 (br. s., 1H), 9.29(br. s., 1H), 8.73 (br. s., 1H), 8.05-7.96 (m, 1H), 6.94 (d, J=8.3 Hz,1H), 6.65 (d, J=2.2 Hz, 1H), 6.60 (dd, J=8.2, 2.3 Hz, 1H), 5.90 (br. s.,1H), 4.07 (d, J=4.7 Hz, 1H), 3.82-3.71 (m, 3H), 3.49-3.36 (m, 3H),3.35-3.24 (m, 4H), 3.15-2.90 (m, 5H), 2.87-2.79 (m, 1H), 2.66-2.54 (m,2H), 2.35-2.17 (m, 3H), 1.99-1.87 (m, 2H), 1.44 (d, J=10.3 Hz, 1H), 1.12(d, J=6.1 Hz, 6H), 1.10-1.03 (m, 1H), 0.73-0.64 (m, 1H), 0.63-0.54 (m,1H), 0.53-0.45 (m, 1H), 0.44-0.36 (m, 1H). LC/MS, m/z=484 [M+H]⁺ (Calc:483).

Compound 135 bis-TFA salt: ¹H NMR (DMSO-d₆) δ: 9.96 (br. s., 1H), 9.38(s, 1H), 8.74 (br. s., 1H), 8.40-8.32 (m, 1H), 6.99 (d, J=8.4 Hz, 1H),6.77 (d, J=2.3 Hz, 1H), 6.67 (dd, J=8.3, 2.3 Hz, 1H), 6.24 (br. s., 1H),4.09 (d, J=5.3 Hz, 1H), 3.86-3.75 (m, 2H), 3.37-3.26 (m, 5H), 3.22-3.07(m, 3H), 2.99 (d, J=8.9 Hz, 1H), 2.88-2.79 (m, 1H), 2.58 (br. s., 4H),2.40-2.23 (m, 2H), 2.05-1.80 (m, 3H), 1.49 (d, J=9.9 Hz, 1H), 1.13 (d,J=5.6 Hz, 6H), 1.10-1.01 (m, 1H), 0.72-0.65 (m, 1H), 0.64-0.55 (m, 1H),0.53-0.44 (m, 1H), 0.44-0.37 (m, 1H). LC/MS, m/z=484 [M+H]⁺ (Calc: 483).

Compound 136 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.21 (s, 1H), 8.65 (br. s.,1H), 8.12 (t, J=5.9 Hz, 1H), 7.29 (dd, J=10.0, 2.1 Hz, 1H), 7.14 (dd,J=8.3, 1.9 Hz, 1H), 6.93-6.86 (m, 2H), 6.62 (d, J=2.3 Hz, 1H), 6.55 (dd,J=8.2, 2.3 Hz, 1H), 5.77 (s, 1H), 4.07 (d, J=5.8 Hz, 2H), 3.99 (d, J=4.1Hz, 1H), 3.28-3.18 (m, 2H, overlapped with water), 3.11-3.01 (m, 2H),2.91 (d, J=9.5 Hz, 1H), 2.79-2.70 (m, 1H), 2.50 (dd, J=13.0, 2.5 Hz,1H), 2.29-2.12 (m, 3H), 1.88 (d, J=8.8 Hz, 2H), 1.38 (d, J=10.7 Hz, 1H),1.06-0.95 (m, 1H), 0.66-0.57 (m, 1H), 0.56-0.47 (m, 1H), 0.46-0.38 (m,1H), 0.38-0.30 (m, 1H) LC/MS, m/z=485 [M+H]⁺ (Calc: 484).

Compound 137 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (br. s., 1H), 8.72-8.62(m, 2H), 7.24 (d, J=7.9 Hz, 1H), 7.21 (d, J=1.3 Hz, 1H), 7.05 (dd,J=7.7, 1.5 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.59(dd, J=8.3, 2.4 Hz, 1H), 6.43 (s, 1H), 4.20 (d, J=5.9 Hz, 2H), 4.04 (d,J=5.0 Hz, 1H), 3.30-3.19 (m, 2H), 3.14-3.04 (m, 1H), 2.92 (d, J=9.8 Hz,1H), 2.81-2.71 (m, 1H), 2.68-2.51 (m, 2H), 2.34-2.17 (m, 5H), 1.93 (dd,J=12.4, 8.2 Hz, 1H), 1.80 (d, J=6.5 Hz, 2H), 1.42 (d, J=10.9 Hz, 1H),1.05-0.94 (m, 1H), 0.66-0.57 (m, 1H), 0.57-0.48 (m, 1H), 0.44-0.28 (m,2H). LC/MS, m/z=481 [M+H]⁺ (Calc: 480).

Compound 138 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.28 (s, 1H), 8.68 (br. s.,1H), 8.55 (t, J=5.5 Hz, 1H), 7.30 (dd, J=7.0, 2.2 Hz, 1H), 7.16-7.09 (m,2H), 6.91 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.59 (dd, J=8.3,2.3 Hz, 1H), 6.44 (s, 1H), 4.32-4.21 (m, 2H), 4.04 (d, J=5.4 Hz, 1H),3.29-3.20 (m, 2H, overlapped with water), 3.14-3.03 (m, 1H), 2.92 (d,J=10.0 Hz, 1H), 2.82-2.71 (m, 1H), 2.68-2.51 (m, 2H, overlapped withDMSO), 2.34-2.19 (m, 5H), 1.93 (dd, J=12.5, 8.2 Hz, 1H), 1.80 (d, J=6.6Hz, 2H), 1.42 (d, J=11.3 Hz, 1H), 1.06-0.94 (m, 1H), 0.66-0.57 (m, 1H),0.56-0.48 (m, 1H), 0.44-0.29 (m, 2H). LC/MS, m/z=481 [M+H]⁺ (Calc: 480).

Compound 139 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.15 (s, 1H), 9.05 (s, 1H),8.69-8.61 (m, 1H), 8.02 (t, J=5.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.60(d, J=2.1 Hz, 1H), 6.56-6.47 (m, 1H), 6.00-5.94 (m, 2H), 5.73 (s, 1H),3.98 (d, J=3.5 Hz, 1H), 3.95-3.82 (m, 2H), 3.24-3.17 (m, 2H, overlappedwith water), 3.09-3.00 (m, 2H), 2.91 (d, J=9.8 Hz, 1H), 2.81-2.71 (m,1H), 2.51-2.45 (m, 2H), 2.30-2.09 (m, 3H), 1.94-1.78 (m, 2H), 1.37 (d,J=11.4 Hz, 1H), 1.05-0.96 (m, 1H), 0.66-0.57 (m, 1H), 0.56-0.47 (m, 1H),0.45-0.38 (m, 1H), 0.38-0.28 (m, 1H). LC/MS, m/z=465 [M+H]⁺ (Calc: 464).

Compound 140 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.17 (s, 1H), 8.70 (s, 1H),8.64 (br. s., 2H), 7.95 (t, J=5.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.61(d, J=2.3 Hz, 1H), 6.56 (d, J=8.0 Hz, 1H), 6.53 (dd, J=8.3, 2.3 Hz, 1H),6.48 (d, J=1.9 Hz, 1H), 6.28 (dd, J=8.0, 1.9 Hz, 1H), 5.73 (s, 1H), 3.98(d, J=4.3 Hz, 1H), 3.94-3.83 (m, 2H), 3.27-3.17 (m, 2H, overlapped withwater), 3.10-2.97 (m, 2H), 2.90 (d, J=9.9 Hz, 1H), 2.79-2.69 (m, 1H),2.50-2.45 (m, 1H, overlapped with DMSO), 2.28-2.09 (m, 3H), 1.85 (d,J=8.9 Hz, 2H), 1.37 (d, J=11.2 Hz, 1H), 1.06-0.95 (m, 1H), 0.65-0.57 (m,1H), 0.55-0.46 (m, 1H), 0.45-0.37 (m, 1H), 0.36-0.30 (m, 1H). LC/MS,m/z=465 [M+H]⁺ (Calc: 464).

Compound 141 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.28 (s, 1H), 9.18 (s, 1H),8.69 (br. s., 1H), 8.55 (t, J=5.6 Hz, 1H), 8.50 (s, 1H), 6.91 (d, J=8.4Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 6.67-6.56 (m, 3H), 6.55-6.45 (m, 2H),4.22-4.09 (m, 2H), 4.04 (d, J=3.9 Hz, 1H), 3.27-3.19 (m, 2H, overlappedwith water), 3.13-3.04 (m, 1H), 2.92 (d, J=10.7 Hz, 1H), 2.81-2.72 (m,1H), 2.71-2.64 (m, 1H), 2.59-2.51 (m, 1H), 2.34-2.15 (m, 2H), 1.91 (dd,J=12.8, 8.3 Hz, 1H), 1.82-1.72 (m, 2H), 1.42 (d, J=10.9 Hz, 1H),1.05-0.94 (m, 1H), 0.66-0.58 (m, 1H), 0.57-0.48 (m, 1H), 0.44-0.36 (m,1H), 0.35-0.28 (m, 1H). LC/MS, m/z=465 [M+H]⁺ (Calc: 464).

Compound 142 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.22 (s, 1H), 9.16 (s, 1H),8.64 (br. s., 1H), 8.05 (t, J=5.9 Hz, 1H), 7.00 (t, J=7.8 Hz, 1H), 6.88(d, J=8.3 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.56-6.51 (m, 2H), 6.49 (s,1H), 6.42 (d, J=7.6 Hz, 1H), 5.74 (s, 1H), 4.05-3.93 (m, 3H), 3.28-3.17(m, 2H, overlapped with water), 3.10-2.99 (m, 2H), 2.91 (d, J=10.8 Hz,1H), 2.78-2.70 (m, 1H), 2.50-2.46 (m, 1H, overlapped with DMSO),2.29-2.10 (m, 3H), 1.93-1.82 (m, 2H), 1.38 (d, J=11.0 Hz, 1H), 1.01 (br.s., 1H), 0.66-0.56 (m, 1H), 0.56-0.47 (m, 1H), 0.46-0.38 (m, 1H),0.38-0.28 (m, 1H). LC/MS, m/z=449 [M+H]⁺ (Calc: 448).

Compound 143 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (s, 1H), 8.73-8.62 (m,2H), 7.05 (tt, J=9.4, 2.3 Hz, 1H), 6.94-6.85 (m, 3H), 6.72 (d, J=2.3 Hz,1H), 6.60 (dd, J=8.3, 2.4 Hz, 1H), 6.29 (s, 1H), 4.26 (d, J=5.9 Hz, 2H),4.04 (d, J=4.8 Hz, 1H), 3.28-3.20 (m, 2H, overlapped with water),3.15-3.06 (m, 1H), 2.92 (d, J=9.4 Hz, 1H), 2.81-2.72 (m, 1H), 2.67-2.51(m, 2H), 2.33-2.18 (m, 2H), 1.96 (dd, J=12.2, 8.4 Hz, 1H), 1.85-1.80 (m,2H), 1.42 (d, J=11.0 Hz, 1H), 1.04-0.95 (m, 1H), 0.65-0.57 (m, 1H),0.56-0.47 (m, 1H), 0.44-0.36 (m, 1H), 0.36-0.28 (m, 1H). LC/MS, m/z=469[M+H]⁺ (Calc: 468).

Compound 144 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (s, 1H), 8.72-8.62 (m,2H), 7.33 (dt, J=10.8, 8.5 Hz, 1H), 7.22 (ddd, J=11.7, 7.9, 2.0 Hz, 1H),7.06-7.00 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.59(dd, J=8.3, 2.4 Hz, 1H), 6.36 (s, 1H), 4.22 (d, J=5.8 Hz, 2H), 4.03 (d,J=4.7 Hz, 1H), 3.29-3.19 (m, 2H, overlapped with water), 3.14-3.04 (m,1H), 2.92 (d, J=9.8 Hz, 1H), 2.81-2.72 (m, 1H), 2.67-2.50 (m, 2H),2.33-2.16 (m, 2H), 1.95 (dd, J=12.2, 8.3 Hz, 1H), 1.85-1.79 (m, 2H),1.42 (d, J=11.2 Hz, 1H), 1.05-0.95 (m, 1H), 0.66-0.57 (m, 1H), 0.57-0.47(m, 1H), 0.43-0.29 (m, 2H). LC/MS, m/z=469 [M+H]⁺ (Calc: 468).

Compound 145 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.17 (br. s., 1H), 8.65 (br.s., 1H), 8.13 (t, J=6.0 Hz, 1H), 7.25 (dt, J=10.8, 8.5 Hz, 1H), 7.07(ddd, J=11.6, 8.0, 2.0 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.81-6.76 (m,1H), 6.61 (d, J=2.3 Hz, 1H), 6.54 (dd, J=8.3, 2.3 Hz, 1H), 5.77 (s, 1H),4.05 (d, J=5.8 Hz, 2H), 3.99 (d, J=4.2 Hz, 1H), 3.28-3.18 (m, 2H),3.10-3.00 (m, 2H), 2.91 (d, J=9.6 Hz, 1H), 2.78-2.71 (m, 1H), 2.50 (dd,J=13.1, 2.5 Hz, 1H), 2.28-2.11 (m, 3H), 1.92-1.84 (m, 2H), 1.38 (d,J=10.7 Hz, 1H), 1.07-0.96 (m, 1H), 0.66-0.57 (m, 1H), 0.56-0.48 (m, 1H),0.46-0.38 (m, 1H), 0.37-0.30 (m, 1H). LC/MS, m/z=469 [M+H]⁺ (Calc: 468).

Compound 146 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.29 (s, 1H), 8.68 (br. s.,1H), 8.61 (t, J=5.7 Hz, 1H), 7.32-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.01(td, J=8.6, 2.2 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H),6.59 (dd, J=8.3, 2.3 Hz, 1H), 6.37 (s, 1H), 4.29-4.18 (m, 2H), 4.03 (d,J=5.0 Hz, 1H), 3.28-3.18 (m, 2H, overlapped with water), 3.13-3.04 (m,1H), 2.91 (d, J=9.7 Hz, 1H), 2.81-2.72 (m, 1H), 2.66-2.57 (m, 1H),2.57-2.49 (m, 1H), 2.33-2.16 (m, 2H), 1.97-1.88 (m, 1H), 1.79 (d, J=6.6Hz, 2H), 1.41 (d, J=10.7 Hz, 1H), 1.05-0.94 (m, 1H), 0.66-0.57 (m, 1H),0.56-0.47 (m, 1H), 0.44-0.28 (m, 2H). LC/MS, m/z=469 [M+H]⁺ (Calc: 468).

Compound 147 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.20 (br. s., 1H), 8.65 (br.s., 1H), 8.09 (t, J=5.8 Hz, 1H), 7.11 (t, J=9.9 Hz, 1H), 6.96-6.90 (m,2H), 6.88 (d, J=8.4 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.55 (dd, J=8.3,2.3 Hz, 1H), 5.77 (s, 1H), 4.07 (d, J=5.7 Hz, 2H), 3.99 (d, J=4.3 Hz,1H), 3.28-3.18 (m, 2H), 3.11-3.00 (m, 2H), 2.91 (d, J=9.6 Hz, 1H),2.78-2.70 (m, 1H), 2.49 (dd, J=13.0, 2.6 Hz, 1H), 2.29-2.11 (m, 3H),1.88 (d, J=9.0 Hz, 2H), 1.38 (d, J=11.1 Hz, 1H), 1.06-0.93 (m, 1H),0.66-0.56 (m, 1H), 0.56-0.47 (m, 1H), 0.46-0.38 (m, 1H), 0.38-0.31 (m,1H). LC/MS, m/z=469 [M+H]⁺ (Calc: 468).

Compound 148 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.18 (s, 1H), 8.66 (br. s.,1H), 8.10 (t, J=5.8 Hz, 1H), 7.37-7.29 (m, 1H), 7.29-7.13 (m, 2H),6.93-6.85 (m, 2H), 6.64 (d, J=2.3 Hz, 1H), 6.55 (dd, J=8.3, 2.3 Hz, 1H),5.78 (s, 1H), 4.13 (d, J=5.8 Hz, 2H), 4.00 (d, J=4.2 Hz, 1H), 3.29-3.18(m, 2H), 3.15-3.02 (m, 2H), 2.92 (d, J=10.1 Hz, 1H), 2.80-2.69 (m, 1H),2.54 (dd, J=13.0, 2.4 Hz, 1H), 2.30-2.12 (m, 3H), 1.91 (d, J=9.6 Hz,2H), 1.39 (d, J=11.2 Hz, 1H), 1.07-0.96 (m, 1H), 0.65-0.57 (m, 1H),0.57-0.47 (m, 1H), 0.46-0.38 (m, 1H), 0.38-0.28 (m, 1H). LC/MS, m/z=514[M+H]⁺ (Calc: 514).

Compound 149 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.37 (s, 1H), 9.17 (s, 1H),8.65 (br. s., 1H), 8.00 (t, J=5.9 Hz, 1H), 6.98-6.92 (m, 1H), 6.88 (d,J=8.4 Hz, 1H), 6.75 (d, J=6.3 Hz, 1H), 6.69-6.61 (m, 3H), 6.54 (dd,J=8.3, 2.3 Hz, 1H), 5.75 (s, 1H), 4.07-3.94 (m, 3H), 3.28-3.18 (m, 2H,overlapped with water), 3.14-3.02 (m, 2H), 2.91 (d, J=10.4 Hz, 1H),2.81-2.69 (m, 1H), 2.50 (dd, J=13.1, 2.8 Hz, 1H, overlapped with DMSO),2.29-2.12 (m, 3H), 1.94-1.81 (m, 2H), 1.38 (d, J=11.0 Hz, 1H), 1.08-0.91(m, 1H), 0.66-0.57 (m, 1H), 0.56-0.47 (m, 1H), 0.46-0.38 (m, 1H),0.38-0.30 (m, 1H). LC/MS, m/z=449 [M+H]⁺ (Calc: 448).

Compound 150 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.19 (s, 1H), 8.72 (br. s.,1H), 8.25 (t, J=5.9 Hz, 1H), 7.46 (t, J=1.9 Hz, 1H), 7.18 (d, J=1.8 Hz,2H), 6.94 (d, J=8.3 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 6.59 (dd, J=8.3,2.4 Hz, 1H), 5.83 (s, 1H), 4.22-4.04 (m, 3H), 3.35-3.24 (m, 2H),3.19-3.08 (m, 2H), 2.98 (d, J=10.3 Hz, 1H), 2.86-2.78 (m, 1H), 2.58-2.53(m, 1H), 2.37-2.19 (m, 3H), 2.03-1.86 (m, 2H), 1.45 (d, J=11.5 Hz, 1H),1.14-1.04 (m, 1H), 0.72-0.64 (m, 1H), 0.63-0.55 (m, 1H), 0.53-0.38 (m,2H). LC/MS, m/z=501 [M+H]⁺ (Calc: 500).

Compound 151 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.19 (s, 1H), 8.73 (br. s.,1H), 8.24 (t, J=5.7 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.35 (dd, J=8.4,2.6 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.66 (d,J=2.3 Hz, 1H), 6.58 (dd, J=8.3, 2.4 Hz, 1H), 5.84 (s, 1H), 4.26-4.12 (m,2H), 4.07 (d, J=4.3 Hz, 1H), 3.35-3.24 (m, 2H), 3.24-3.08 (m, 2H), 2.98(d, J=10.7 Hz, 1H), 2.87-2.77 (m, 1H), 2.55 (dd, J=12.9, 3.1 Hz, 2H),2.37-2.17 (m, 3H), 2.05-1.87 (m, 2H), 1.45 (d, J=11.5 Hz, 1H), 1.13-1.04(m, 1H), 0.72-0.64 (m, 1H), 0.63-0.56 (m, 1H), 0.53-0.46 (m, 1H),0.45-0.36 (m, 1H). LC/MS, m/z=501 [M+H]⁺ (Calc: 500).

Compound 152 TFA salt: ¹H NMR (DMSO-d₆) δ: 9.16 (s, 1H), 8.65 (br. s.,1H), 8.14 (t, J=6.0 Hz, 1H), 7.31-7.18 (m, 2H), 7.13 (s, 1H), 6.93 (d,J=7.4 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.54 (dd,J=8.3, 2.4 Hz, 1H), 5.76 (s, 1H), 4.11-4.04 (m, 2H), 3.99 (d, J=4.6 Hz,1H), 3.29-3.15 (m, 2H, overlapped with water), 3.11-3.00 (m, 2H), 2.91(d, J=10.1 Hz, 1H), 2.79-2.69 (m, 1H), 2.49 (dd, J=12.9, 2.9 Hz, 1H),2.29-2.11 (m, 3H), 1.96-1.81 (m, 2H), 1.38 (d, J=11.3 Hz, 1H), 1.06-0.93(m, 1H), 0.64-0.57 (m, 1H), 0.56-0.47 (m, 1H), 0.45-0.38 (m, 1H),0.37-0.28 (m, 1H). LC/MS, m/z=467 [M+H]⁺ (Calc: 466).

Example 22

The following Tables provide results on the efficacy of binding andactivity response of exemplified Compounds of the Invention at theORL-1, μ-, δ-, and κ-opioid receptors.

In TABLE 3, binding affinity of certain Compounds of the Invention tothe ORL-1, μ-, δ-, and κ-opioid receptors was determined as describedabove.

In TABLE 4, activity response of certain Compounds of the Invention tothe μ- and κ-opioid receptors was determined as described above forfunctional assays using HEK-293 or CHO cells.

TABLE 3 Binding Affinity of Certain Compounds of the Invention K_(i)(nM) Compd. Opioid Receptor No. ORL-1 μ κ δ 6 10273 ± 2145 19.7 ± 4.680.098 ± 0.032 7714 ± 1278 7 23.6 ± 5.56  0.13 ± 0.018 11  2982 ± 466.1182.0 ± 29.2  12  0.53 ± 0.076  0.30 ± 0.056 16 55.6 ± 11.0 17.3 ± 6.1931 >20 μM 10.2 ± 3.58 0.84 ± 0.26 33  1.39 ± 0.082 0.75 ± 0.13 34 0.083± 0.014 38  0.16 ± 0.044 42  0.40 ± 0.024 0.37 ± 0.13 93  0.64 ± 0.071108 9.29 ± 2.14

TABLE 4 Activity Response of Certain Compounds of the Invention OpioidReceptor μ κ δ Compd EC₅₀ E_(max) EC₅₀ E_(max) EC₅₀ E_(max) No. (nM) (%)(nM) (%) (nM) (%) 6 >20 μM 0.00 0.86 ± 0.16 48.6 ± 0.98 7 >20 μM 1.00 ±0.00 0.80 ± 0.26 57.5 ± 1.66 12 >20 μM 1.00 ± 0.00 2.95 ± 1.06 82.7 ±1.20 15 >20 μM 7.00 16 >20 μM 1.00 ± 0.00 12.4 ± 3.66 38.0 ± 2.04 22 >20μM 1.00 ± 0.00 25.7 ± 4.99 77.0 ± 1.00 25 616.2 ± 40.9  12.0 ± 2.0828 >20 μM 7.50 30 >20 μM 1.00 ± 0.00 2.49 ± 0.090 50.7 ± 0.33 31 >20 μM1.00 ± 0.00 6.95 ± 0.97 35.3 ± 2.19 75.5 ± 13.6  32.0 ± 3.49 33 >20 μM1.00 7.03 ± 0.82 43.3 ± 0.33 34 3.75 ± 0.66 40.0 ± 1.53 0.094 ± 0.011101.7 ± 2.73  36 >20 μM 1.00 ± 0.00 2.24 ± 0.46 94.7 ± 3.71 37 >20 μM1.00 1.74 ± 0.39 32.5 ± 2.10 38 0.62 ± 0.12 56.5 ± 2.60 0.43 ± 0.04896.3 ± 3.18 1.56 ± 0.055 50.1 ± 1.25 39 37.5 ± 12.6 15.0 ± 1.73 40 >20μM 1.00 41 >20 μM 1.00 1.74 ± 0.47 35.8 ± 3.07 42 >20 μM 1.00 0.32 ±0.059 98.3 ± 1.33 43 8.35 ± 1.80 11.0 ± 0.82 45  0.38 ± 0.044 43.3 ±4.84 46 >20 μM 0.00 0.20 ± 0.072 32.0 ± 5.00 47  2.76 ± 0.082 86.0 ±3.46 0.030 ± 0.01 88.8 ± 10.0 48 >20 μM −1.00 ± 0.00  49 6.17 ± 1.9810.5 ± 0.29 51  0.49 ± 0.040 43.0 ± 3.06 64 >20 μM 3.50 77 580.3 ± 131.419.6 ± 5.65 78 308.0 ± 93.0  27.4 ± 1.03 79 >20 μM −1.00  80 >20 μM 1.0081 >20 μM 19.0 ± 1.53 82 >20 μM 1.00 ± 0.00 83 >20 μM 0.00 84 71.7 ±23.7 19.7 ± 1.67 85 >20 μM −1.00  86 28.8 ± 10.5 12.8 ± 0.63 87 >20 μM1.00 88 >20 μM 0.00 89 >20 μM 4.50 90 >20 μM 8.14 ± 1.30 91 >20 μM −1.00± 0.00  92 >20 μM −1.00  93 3.95 ± 0.65 28.8 ± 4.91 1.52 ± 0.17 81.5 ±1.27 94 >20 μM 10.6 ± 3.41

The in vitro test results of Tables 3 and 4 show that representativeCompounds of the Invention generally have high binding affinity foropioid receptors, and that these compounds activate these receptors aspartial to full agonists. Compounds of the Invention are thereforeexpected to be useful to treat Conditions, particularly pain, that areresponsive to the activation of one or more opioid receptors.

Example 23

The following TABLE 5 provides results on the activity response ofcertain Compounds of the Invention at the μ- and κ-opioid receptorsdetermined as described above using U-2 OS cells.

TABLE 5 Activity Response of Certain Compounds of the Invention OpioidReceptor Compd. μ κ No. EC₅₀ (nM) E_(max) (%) EC₅₀ (nM) E_(max) (%) 616.0 ± 0.91 57.0 ± 2.08 0.87 ± 0.16  98.0 ± 3.21 7 8.94 ± 1.31 56.3 ±2.60 1.16 ± 0.16 101.3 ± 3.67 11 1358 ± 49.8  103.3 ± 1.67 12 1.22 ±0.27 55.6 ± 3.83 1.70 ± 0.26 108.0 ± 3.51 14 125.8 ± 37.7  26.7 ± 2.40147.3 ± 11.6  100.0 ± 2.52 15 342.6 ± 110.4 31.6 ± 3.21 2896 ± 82.3  79.7 ± 5.81 16 4.75 ± 0.62 31.8 ± 3.07 13.2 ± 1.86  90.7 ± 5.81 19 2965 ± 863.8 29.3 ± 5.93  4721 ± 150.1  97.7 ± 0.67 20 1233 ± 83.5 43.3 ± 2.40  4398 ± 357.1  87.7 ± 4.33 21 >20 μM 8.67 ± 1.76  5594 ±738.2  90.0 ± 2.08 22 110.6 ± 14.1  20.7 ± 2.40 25.4 ± 2.09 100.7 ± 1.7625 227.5 ± 25.4  54.3 ± 4.10 234.1 ± 28.5  107.0 ± 4.16 26  1131 ± 116.863.0 ± 5.77 828.9 ± 100.4 106.3 ± 2.03 28 325.7 ± 77.9  35.7 ± 5.49178.6 ± 16.4  106.7 ± 0.88 29 7.78 ± 1.63 22.0 ± 1.73  0.62 ± 0.040106.7 ± 3.18 30 1.62 ± 0.41 32.0 ± 1.15  1.26 ± 0.050 100.3 ± 1.20 312.35 ± 0.32 49.0 ± 3.76  2.62 ± 0.024  87.5 ± 5.04 33 3.84 ± 0.21 45.7 ±0.67 3.18 ± 0.46 102.7 ± 3.48 34  0.25 ± 0.027 94.0 ± 0.58 0.020 ± 0.00  93.3 ± 3.18 35 19.7 ± 5.27 29.7 ± 0.33 7.75 ± 0.41 110.7 ± 2.96 36 1.96± 0.27 47.7 ± 3.18  0.27 ± 0.019 108.3 ± 4.10 37 8.48 ± 2.28 30.7 ± 2.670.97 ± 0.11 105.3 ± 0.88 38  0.25 ± 0.024 77.7 ± 2.40 0.065 ± 0.01 105.3 ± 3.18 39 11.1 ± 0.28 42.0 ± 1.00  1.85 ± 0.097  91.7 ± 1.86 40 1.45 ± 0.068 29.3 ± 1.33  0.73 ± 0.070  97.7 ± 1.86 41 4.19 ± 1.02 25.3± 1.33  1.02 ± 0.080  86.7 ± 6.74 42 1.33 ± 0.12 35.0 ± 1.15  1.27 ±0.076  87.7 ± 4.63 43 4.55 ± 0.14 41.3 ± 2.03  0.67 ± 0.020 101.7 ± 5.9044 3.75 ± 0.35 28.3 ± 1.86  0.26 ± 0.033  94.7 ± 7.13 45  0.14 ± 0.01887.0 ± 0.58 0.018 ± 0.00  100.0 ± 4.62 46  0.91 ± 0.050 38.0 ± 1.73 0.11± 0.01 106.3 ± 4.26 47 0.050 ± 0.01  98.8 ± 1.49 0.015 ± 0.00   95.0 ±5.29 48 3.12 ± 0.27 40.0 ± 1.53 1.46 ± 0.29 106.3 ± 2.33 49 3.73 ± 0.2342.3 ± 1.45  0.82 ± 0.099 108.3 ± 4.70 50 6.90 ± 0.54 23.3 ± 1.86 1.95 ±0.33 107.7 ± 0.88 51  0.13 ± 0.015 87.7 ± 1.20 0.047 ± 0.00  102.0 ±2.31 56 10.4 ± 2.03 16.0 ± 1.53 20.8 ± 1.79  97.8 ± 3.67 57 2.79 ± 0.7637.7 ± 6.69 5.88 ± 0.79  90.3 ± 2.60 58 14.3 ± 5.43 21.7 ± 5.49 24.3 ±5.67  93.7 ± 4.48 59 22.6 ± 6.31 25.7 ± 0.33 26.0 ± 2.61 105.3 ± 4.33 6217.0 ± 3.31 25.0 ± 0.58 23.6 ± 1.09 108.7 ± 3.67 64 6.96 ± 0.27 48.7 ±0.33 3.51 ± 0.16 100.7 ± 4.98 66 29.0 ± 4.29 15.5 ± 1.50 167.9 ± 8.15  77.3 ± 0.88 75 >20 μM 2.00 1261 ± 74.6   69.0 ± 6.03 76 >20 μM 2.00922.9 ± 31.9   81.0 ± 6.66 77 388.9 ± 74.0  85.0 ± 2.52  1148 ± 220.5 65.3 ± 6.44 78 89.3 ± 14.6 94.7 ± 2.40 973.1 ± 135.7  89.7 ± 4.84

The in vitro test results of Table 5 show that representative Compoundsof the Invention activate these receptors as partial to full agonists.Compounds of the Invention are therefore expected to be useful to treatConditions, particularly pain, that are responsive to the activation ofone or more opioid receptors.

Example 24

The following TABLE 6 provides results on the activity response ofcertain Compounds of the Invention at the μ- and κ-opioid receptorsdetermined as described above using HEK-293 cells.

TABLE 6 Activity Response of Certain Compounds of the Invention OpioidReceptor Compd. μ κ No. EC₅₀ (nM) E_(max) (%) EC₅₀ (nM) E_(max) (%)95 >20 μM  1.00 96 14.4 ± 2.55 14.2 ± 2.50 97 28.1 ± 1.54 90.3 ± 0.88 98 1295 ± 222.9 26.7 ± 0.67 99 243.6 ± 29.5  73.3 ± 1.20 100  1095 ± 187.850.3 ± 0.33 101 1.58 ± 0.22 96.7 ± 2.19 102 655.4 ± 128.3 49.5 ± 4.94103 389.3 ± 73.3  68.0 ± 9.54 104 2932 ± 1083 52.0 ± 3.51 107 10.8 ±0.83 94.7 ± 0.33 108 12.4 ± 2.76 83.3 ± 5.17 137.6 ± 35.0 40.6 ± 3.30109 80.4 ± 14.1 70.4 ± 0.98 110  8413 ± 955.8 35.2 ± 0.76 111  3167 ±492.8 35.1 ± 1.06 112 10172 ± 241.1  38.8 ± 1.54 113 >20 μM −1.00 ±0.00  114 8437 ± 1544 23.0 ± 1.54 115 917.0 ± 131.3 35.0 ± 1.14 116 3.45± 0.16 23.6 ± 1.05 117 >20 μM −1.21 ± 0.21  118 174.5 ± 9.90  13.2 ±1.17 119 13.4 ± 4.19 18.4 ± 1.55 120 631.3 ± 152.0 22.7 ± 1.92 121 1088± 70.2  29.3 ± 1.78 122 >20 μM 0.33 ± 0.67 123  2919 ± 377.8 10.5 ± 1.07124 >20 μM 1.93 ± 2.93 125 >20 μM −1.00 126 >20 μM −1.00 127 >20 μM−1.00 128 >20 μM −1.00 129 >20 μM  1.00 130 >20 μM  0.00 131 >20 μM 1.00 132 >20 μM −1.00 133 14.2 ± 3.73 29.8 ± 1.22 134 92.0 ± 19.7 9.53± 0.90 135 10.3 ± 1.03 19.7 ± 0.89 136 >20 μM −0.33 ± 0.67  137  0.45 ±0.061 55.5 ± 0.31 138  0.71 ± 0.068 52.4 ± 1.72 139 >20 μM −1.00 140 >20μM 0.33 ± 0.67 141 1.17 ± 0.10 47.4 ± 0.83 142 >20 μM  0.00 143 2.09 ±0.45 39.9 ± 1.01 145 >20 μM −1.00 146 2.22 ± 0.41 28.3 ± 1.13 147 >20 μM−1.00 148 >20 μM  1.00 149 >20 μM  0.00 150 >20 μM −1.00 151 >20 μM−1.00 152 >20 μM 4.45 ± 3.18

The in vitro test results of Table 6 show that representative Compoundsof the Invention activate these receptors as partial to full agonists.Compounds of the Invention are therefore expected to be useful to treatConditions, particularly pain, that are responsive to the activation ofone or more opioid receptors.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents, patent applications, and publications cited herein arefully incorporated by reference herein in their entirety.

1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ ishydrogen, hydroxy, halo, cyano, carboxy, or aminocarbonyl; or alkyl,alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein saidaryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R⁴ groups;or —O-PG, wherein PG is a hydroxyl protecting group; R² is (a) hydrogenor carboxamido; or (b) alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R⁴ groups; R³ ishydrogen, hydroxy, or halo; or alkoxy, alkylamino, or dialkylamino, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups; each R⁴ is independently selected fromthe group consisting of hydroxy, halo, alkyl, haloalkyl, cyano, nitro,amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; Gis selected from the group consisting of G¹, G², G³, and G⁴, wherein G¹is —C(═O)OR⁵, G² is —C(═O)NR⁶R⁷, G³ is —NR⁸R⁹, and G⁴ is —CN, wherein R⁵is hydrogen or alkyl; R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylkyl,aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(aminocarbonyl)alkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, carboxyalkyl, (alkoxycarbonyl)alkyl, andguanidinoalkyl, wherein the cycloalkyl, cycloalkenyl, heterocyclo, aryl,and heteroaryl portions are optionally substituted with one or more R⁴groups; or R⁶ and R⁷ together with the nitrogen atom to which they areattached form an optionally substituted heterocyclic ring; R⁸ and R⁹ areeach independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl,arylalkyl, heteroarylalkyl, (cycloalkyl)-C(═O)—, (cycloalkenyl)-C(═O)—,heterocyclo-C(═O)—, aryl-C(═O)—, heteroaryl-C(═O)—,(cycloalkyl)alkyl-C(═O)—, (cycloalkenyl)alkyl-C(═O)—,(heterocyclo)alkyl-C(═O)—, arylalkyl-C(═O)—, (heteroaryl)alkyl-C(═O)—,(cycloalkyl)-NR¹⁰—C(═O)—, (cycloalkenyl)-NR¹⁰—C(═O)—,heterocyclo-NR¹⁰—C(═O)—, aryl-NR¹⁰—C(═O)—, heteroaryl-NR¹⁰—C(═O)—,(cycloalkyl)alkyl-NR¹⁰—C(═O)—, (cycloalkenyl)alkyl-NR¹⁰—C(═O)—,(heterocyclo)alkyl-NR¹⁰—C(═O)—, arylalkyl-NR¹⁰—C(═O)—,(heteroaryl)alkyl-NR¹⁰—C(═O)—, (cycloalkyl)-SO₂—, (cycloalkenyl)-SO₂—,heterocyclo-SO₂—, aryl-SO₂—, heteroaryl-SO₂—, (cycloalkyl)alkyl-SO₂—,(cycloalkenyl)alkyl-SO₂—, (heterocyclo)alkyl-SO₂—, arylalkyl-SO₂—,(heteroaryl)alkyl-SO₂—, R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—,R^(10a)—SO₂—, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(aminocarbonyl)alkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, carboxyalkyl, (alkoxycarbonyl)alkyl, andguanidinoalkyl, wherein the cycloalkyl, cycloalkenyl, heterocyclo, aryl,and heteroaryl portions are optionally substituted with one or more R⁴groups; wherein R¹⁰ is hydrogen or alkyl; and R^(10a) is alkyl, alkenyl,or alkynyl; or R¹⁰ and R^(10a) together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclic ring; andR⁸ and R⁹ together with the nitrogen atom to which they are attachedform an optionally substituted heterocyclic ring.
 2. A compound ofFormula IA:

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ ishydrogen, hydroxy, halo, cyano, carboxy, or aminocarbonyl; or alkyl,alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein saidaryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R⁴ groups;or —O-PG, wherein PG is a hydroxyl protecting group; R² is (a) hydrogenor carboxamido; or (b) alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R⁴ groups; R³ ishydrogen, hydroxy, or halo; or alkoxy, alkylamino, or dialkylamino, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups; each R⁴ is independently selected fromthe group consisting of hydroxy, halo, alkyl, haloalkyl, cyano, nitro,amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; Gis selected from the group consisting of G¹, G², G³, and G⁴, wherein G¹is —C(═O)OR⁵, G² is —C(═O)NR⁶R⁷, G³ is —NR⁸R⁹, and G⁴ is —CN, wherein R⁵is hydrogen or alkyl; R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(aminocarbonyl)alkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, carboxyalkyl, (alkoxycarbonyl)alkyl,guanidinoalkyl, hydroxyalkyl, and alkoxyalkyl, wherein the cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl portions are optionallysubstituted with one or more R⁴ groups; or R⁶ and R⁷ together with thenitrogen atom to which they are attached form an optionally substitutedheterocyclic ring; R⁸ and R⁹ are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,(cycloalkyl)-C(═O)—, (cycloalkenyl)-C(═O)—, heterocyclo-C(═O)—,aryl-C(═O)—, heteroaryl-C(═O)—, (cycloalkyl)alkyl-C(═O)—,(cycloalkenyl)alkyl-C(═O)—, (heterocyclo)alkyl-C(═O)—, arylalkyl-C(═O)—,(heteroaryl)alkyl-C(═O)—, (cycloalkyl)-NR¹⁰—C(═O)—,(cycloalkenyl)-NR¹⁰—C(═O)—, heterocyclo-NR¹⁰—C(═O)—, aryl-NR¹⁰—C(═O)—,heteroaryl-NR¹⁰—C(═O)—, (cycloalkyl)alkyl-NR¹⁰—C(═O)—,(cycloalkenyl)alkyl-NR¹⁰—C(═O)—, (heterocyclo)alkyl-NR¹⁰—C(═O)—,arylalkyl-NR¹⁰—C(═O)—, (heteroaryl)alkyl-NR¹⁰—C(═O)—, (cycloalkyl)-SO₂—,(cycloalkenyl)-SO₂—, heterocyclo-SO₂—, aryl-SO₂—, heteroaryl-SO₂—,(cycloalkyl)alkyl-SO₂—, (cycloalkenyl)alkyl-SO₂—,(heterocyclo)alkyl-SO₂—, arylalkyl-SO₂—, (heteroaryl)alkyl-SO₂—,R^(10a)—C(═O)—, R^(10a)—NR¹⁰—C(═O)—, R^(10a)—SO₂—, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (aminocarbonyl)alkyl,(alkylaminocarbonyl)alkyl, (dialkylaminocarbonyl)alkyl, carboxyalkyl,(alkoxycarbonyl)alkyl, guanidinoalkyl, hydroxyalkyl, and alkoxyalkyl,wherein the cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroarylportions are optionally substituted with one or more R⁴ groups; whereinR¹⁰ is hydrogen or alkyl; and R^(10a) is alkyl, alkenyl, or alkynyl; orR¹⁰ and R^(10a) together with the nitrogen atom to which they areattached form an optionally substituted heterocyclic ring; and R⁸ and R⁹together with the nitrogen atom to which they are attached form anoptionally substituted heterocyclic ring.
 3. The compound of claim 1,having Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹,R², R³, and G are as defined in claim
 2. 4. (canceled)
 5. The compoundof claim 2, having Formula IV or Formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹,R², R³, and G are as defined in claim
 2. 6-11. (canceled)
 12. Thecompound of claim 2, or a pharmaceutically acceptable salt or solvatethereof, wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxy, oraminocarbonyl; or alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, oralkynyloxy, any of which is optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R⁴ groups.
 13. The compound of claim 12, or apharmaceutically acceptable salt or solvate thereof, wherein R¹ ishydroxy or unsubstituted C₁₋₆ alkoxy. 14-19. (canceled)
 20. The compoundof claim 2, or a pharmaceutically acceptable salt or solvate thereof,wherein R² is cyclopropyl(C₁₋₄)alkyl, cyclobutyl(C₁₋₄)alkyl,cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl, optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄alkoxycarbonyl.
 21. The compound of claim 2, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² is C₁₋₄ alkyl, which isunsubstituted or substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of hydroxy, C₁₋₄ alkyl,halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino,carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl. 22-23. (canceled)
 24. Thecompound of claim 2, or a pharmaceutically acceptable salt or solvatethereof, wherein R³ is hydroxy, unsubstituted C₁₋₆ alkoxy, or C₁₋₆alkoxy substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, halo(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl.
 25. (canceled)
 26. The compound of claim 2, or apharmaceutically acceptable salt or solvate thereof, wherein G is G¹,which is —C(═O)OR⁵, wherein R⁵ is hydrogen or C₁₋₄ alkyl.
 27. (canceled)28. The compound of claim 2, or a pharmaceutically acceptable salt orsolvate thereof, wherein G is G², which is —C(═O)NR⁶R⁷, wherein R⁶ ishydrogen or C₁₋₆ alkyl, and R⁷ is selected from the group consisting ofhydrogen C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkenyl, 5- or 6-membered heterocyclo, phenyl 5- or 6-memberedheteroaryl, (C₃₋₇ cycloalkyl)(C₁₋₆)alkyl, (C₃₋₇cycloalkenyl)(C₁₋₆)-alkyl, (5- or 6-membered heterocyclo)(C₁₋₆)-alkyl,phenyl(C₁₋₆)alkyl, (5- or 6-membered heteroaryl)(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, (C₁₋₆ alkylamino)(C₁₋₆)alkyl, (di(C₁₋₆alkyl)amino)(C₁₋₆)alkyl, (aminocarbonyl)(C₁₋₆)alkyl, (C₁₋₆alkylaminocarbonyl)(C₁₋₆)alkyl, (di(C₁₋₆)alkylaminocarbonyl)(C₁₋₆)alkyl,carboxy(C₁₋₆)alkyl, (C₁₋₆ alkoxycarbonyl)(C₁₋₆)alkyl,guanidino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, and (C₁₋₆)alkoxy(C₁₋₆)alkyl,wherein the cycloalkyl, cycloalkenyl, heterocyclo, phenyl, andheteroaryl portions are optionally substituted with one or more R⁴groups. 29-31. (canceled)
 32. The compound of claim 28, or apharmaceutically acceptable salt or solvate thereof, wherein G² isselected from the group consisting of

wherein m is independently 0, 1, 2, or 3, and R¹¹, R¹², and R¹³ are eachindependently selected from the group consisting of hydrogen, hydroxy,halogen, and C₁₋₄ alkyl.
 33. The compound of claim 28, or apharmaceutically acceptable salt or solvate thereof, wherein G² isselected from the group consisting of


34. (canceled)
 35. The compound of compound of claim 2, or apharmaceutically acceptable salt or solvate thereof, wherein R⁶ and R⁷together with the nitrogen atom to which they are attached form anoptionally substituted 3-7 membered heterocyclic ring.
 36. (canceled)37. The compound of claim 35, or a pharmaceutically acceptable salt orsolvate thereof, wherein G is G², wherein R⁶ and R⁷ together with thenitrogen atom to which they are attached form a pyrrolidinyl, apiperidinyl, a piperazinyl, a morpholinyl, a thiomorpholinyl, or adioxidothiomorpholinyl ring, which is unsubstituted or substituted with1, 2, or 3 substituents each independently selected from the groupconsisting of hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro,amino, aminocarbonyl, (C₁₋₄ alkylamino)carbonyl, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, pyrrolidin-1-yl, piperidin-1-yl, andphenyl, wherein said phenyl is optionally substituted with 1, 2, or 3independently selected R⁴ groups.
 38. The compound of claim 37, or apharmaceutically acceptable salt or solvate thereof, wherein G² isselected from the group consisting of


39. The compound of claim 2, or a pharmaceutically acceptable salt orsolvate thereof, wherein G is G³, which is —NR⁸R⁹, wherein R⁸ and R⁹both are hydrogen; or R⁸ is hydrogen, and R⁹ is

or R⁵ and R⁹ are both

wherein each R¹⁵ is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₄alkyl. 40-46. (canceled)
 47. The compound ofclaim 2, or a pharmaceutically acceptable salt or solvate thereof,wherein G is G³, wherein R⁸ and R⁹ together with the nitrogen atom towhich they are attached form an optionally substituted 3-7 memberedheterocyclic ring. 48-49. (canceled)
 50. The compound of claim 2, or apharmaceutically acceptable salt or solvate thereof, wherein R¹ ishydroxy or unsubstituted C₁₋₆ alkoxy; R² is unsubstituted C₁₋₄ alkyl;C₁₋₄ alkyl substituted with halo(C₁₋₄)alkyl; or cyclopropyl(C₁₋₄)alkyl,cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl,optionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, C₁₋₄ alkyl, halo,halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy,C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl; and R³ is hydrogen or hydroxy. 51.(canceled)
 52. The compound of claim 2, selected from the groupconsisting of(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2-guanidinoethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(4-guanidinobutyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-methyl12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxylate;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxylicacid;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxylicacid;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)-cyclopenta[a]naphthalene-2-carboxylicacid;((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-yl)(pyrrolidin-1-yl)methanone;((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-yl)(pyrrolidin-1-yl)methanone;(2R,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a-ol;(2R,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a,8-diol;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carbonitrile;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carbonitrile;(2S,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-8-methoxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a-ol;(2S,3aS,4R,9bS)-2-amino-12-(cyclopropylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a,8-diol;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-benzyl-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-N-benzyl-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-isobutyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-isobutyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(4-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(4-chlorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(4-fluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(piperidin-1-yl)methanone;((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(piperidin-1-yl)methanone;((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(morpholino)methanone;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N,N-diethyl-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N,N-dimethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(2-amino-2-oxoethyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;2-((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamido)aceticacid;(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;N-((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)benzamide;(2R,3aS,4R,9bS)-2-(benzylamino)-12-(cyclopropylmethyl)-2,3,4,5-tetrahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a,8(1H)-diol;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-2-(dibenzylamino)-2,3,4,5-tetrahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-3a,8(1H)-diol;N-((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)benzamide;1-((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)-3-phenylurea;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(3-morpholinopropyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(4-phenylpiperazin-1-yl)methanone;((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(thiomorpholino)methanone;((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-3-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-4-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(3-morpholinopropyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(pyridin-3-ylmethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;and((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(1,1-dioxidothiomorpholino)methanone;N-((2R,3aS,4R,9bR)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)benzenesulfonamide;((2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(4-phenylpiperazin-1-yl)methanone;(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(2,4-dihydroxybenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-N-(3,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-3a,8-dihydroxy-N-isobutyl-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-benzyl-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-N-benzyl-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-N-(2,4-dichlorobenzyl)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-N-phenethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;N-((2S,3aS,4R,9bR)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)benzamide;N-((2R,3aS,4R,9bR)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)benzamide;((2R,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(morpholino)methanone;(2R,3aS,4R,9bS)-3a,8-dihydroxy-12-methyl-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(2-(dimethylamino)ethyl)-3a,8-dihydroxy-N,12-dimethyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-3a,8-dihydroxy-N-(2-hydroxyethyl)-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-3a,8-dihydroxy-N-(2-hydroxyethyl)-12-methyl-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-N2-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2,8-dicarboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-N2-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2,8-dicarboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-N2-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2,8-dicarboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a-hydroxy-N2-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2,8-dicarboxamide;(2R,3aS,4R,9bS)-8-cyano-12-(cyclopropylmethyl)-3a-hydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-8-cyano-12-(cyclopropylmethyl)-3a-hydroxy-N-(4-methylbenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-8-cyano-12-(cyclopropylmethyl)-3a-hydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-8-cyano-12-(cyclopropylmethyl)-3a-hydroxy-N-(2-morpholinoethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,3-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(3-chloro-2-methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(3-chloro-4-methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(2-chloro-4-hydroxybenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(3-chloro-4-hydroxybenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(4-chlorophenethyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-dichlorophenethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dichlorophenethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;((2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalen-2-yl)(4-isopropylpiperazin-1-yl)methanone;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(2-(piperidin-1-yl)ethyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)ethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)ethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(4-chloro-2-fluorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-N-(3-chloro-4-methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-N-(3-chloro-2-methylbenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,3-dihydroxybenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(3-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2S,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-N-(2-chlorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-3a,8-dihydroxy-N-(2-hydroxybenzyl)-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(3,5-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;(2R,3aS,4R,9bS)-12-(cyclopropylmethyl)-N-(2,5-dichlorobenzyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;and(2R,3aS,4R,9bS)-N-(3-chlorobenzyl)-12-(cyclopropylmethyl)-3a,8-dihydroxy-1,2,3,3a,4,5-hexahydro-4,9b-(epiminoethano)cyclopenta[a]naphthalene-2-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.
 53. (canceled)54. A pharmaceutical composition, comprising a therapeutically effectiveamount of a compound of claim 2, or a pharmaceutically acceptable saltor solvate thereof, and one or more pharmaceutically acceptablecarriers. 55-58. (canceled)
 59. A method of treating pain, constipation,diarrhea, pruritis, an addictive disorder, withdrawal from alcoholaddiction or withdrawal from drug addiction in a patient, comprisingadministering an effective amount of a compound of claim 2, or apharmaceutically acceptable salt or solvate thereof, to the patient inneed thereof.
 60. The method of claim 59, wherein the method is fortreating pain, wherein said pain is acute pain, chronic pain or surgicalpain, and said chronic pain is selected from the group consisting ofneuropathic pain, postoperative pain, and inflammatory pain. 61-63.(canceled)
 64. A method of modulating one or more opioid receptors in apatient, comprising administering to the patient an effective amount ofa compound as claimed in claim 2, or a pharmaceutically acceptable saltor solvate thereof, wherein a μ- or κ-opioid receptor is modulated, orboth the μ- and κ-opioid receptors are modulated. 65-91. (canceled)